Cyanoquinoline derivatives

ABSTRACT

Disclosed is a compound of formula I, a stereoisomer thereof, a cis-trans-isomer thereof, a tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, a solvate thereof or a prodrug thereof, 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1 , R 2 , R 3  and R 4  are each as defined in the present application.

FIELD

The present application is directed to organic chemistry andpharmaceutical chemistry.

BACKGROUND

In worldwide, the tumor, including cancer, is one of the major factorsleading to death. Although there is a notable development in thediscovery of novel methods for treating tumor, the major selections fortherapy are still the surgery operation, chemotherapy and radiotherapy.The three therapeutic treatment methods can be used alone or incombination. However, the surgery operation and radiotherapy generallyare useful for patients, of which the tumor type has been identified.There are limits of the surgery operation and radiotherapy for treatingpatients, of which the tumor has spread. The chemotherapy is generallyuseful for treating patients having metastatic cancer or diffusecarcinoma, such as leukemia. Although the chemotherapy has therapeuticvalues, it usually does not cure the diseases because cancer cells ofpatients are tolerant to the drugs of chemotherapy.

Therefore, there is a need for novel chemotherapeutants to treat tumor.In this regard, different researchers are doing continuous efforts todiscover novel potential effective chemotherapeutic drugs.

SUMMARY

In one aspect, the present application is directed to a compound offormula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof,

wherein:

R¹ is selected from the group consisting of substituted or unsubstitutedalkylacylamino, substituted or unsubstituted alkenylacylamino,substituted or unsubstituted alkynylacylamino, substituted orunsubstituted arylacylamino, substituted or unsubstituted amino, andsubstituted or unsubstituted alkoxy;

R² and R³ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted aralkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl;

or R² and R³ together with nitrogen atom to which they are attached formsubstituted or unsubstituted heterocyclyl; and

R⁴ is substituted or unsubstituted heterocyclyl, or substituted orunsubstituted heteroaryl.

In another aspect, the present application is directed to a compound offormula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof,

wherein:

R¹ is selected from the group consisting of C₁-C₆ alkylacylamino, C₂-C₆alkenylacylamino, C₂-C₆ alkynylacylamino, C₆-C₁₈ arylacylamino, C₁-C₆alkyl-substituted amino, C₁-C₆ alkoxy;

R² and R³ are each independently selected from the group consisting ofhydrogen, C₇-C₂₄ aralkyl, substituted or unsubstituted C₆-C₁₈ aryl,substituted or unsubstituted C₅-C₁₈ heteroaryl, wherein a substituent onthe aryl is selected from the group consisting of C₂-C₆ alkynyl,halogen, C₇-C₂₄ aralkyloxy, C₆-C₂₄ heteroaralkyloxy, C₆-C₁₈ aryloxy, andC₅-C₁₈ heteroaryloxy, and a substituent on the heteroaryl is selectedfrom C₇-C₂₄ aralkyl, C₆-C₁₈ arylacylamino, C₆-C₁₈ arylsulfonylamino,C₅-C₁₈ heteroaryl acylamino, C₃-C₁₀ cycloalkylacylamino, C₆-C₁₈arylaminoacyl, C₇-C₂₄ aralkyloxy, C₆-C₂₄ heteroaralkyloxy, and C₆-C₁₈aryloxy;

or R² and R³ together with nitrogen atom to which they are attached formsubstituted or unsubstituted C₃-C₁₈ heterocyclyl; and

R⁴ is C₃-C₁₈ heterocyclyl or C₅-C₁₈ heteroaryl.

In another aspect, the present application is directed to apharmaceutical composition, comprising a therapeutically effectiveamount of a compound of formula I, a stereoisomer thereof, acis-trans-isomer thereof, a tautomer thereof, or a mixture thereof, or apharmaceutically acceptable salt thereof, a solvate thereof or prodrugthereof, and a pharmaceutically acceptable carrier.

In yet another aspect, the present application is directed to a methodfor treating and/or preventing a tumor in a mammal, comprisingadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of formula I, a stereoisomer thereof, acis-trans-isomer thereof, a tautomer thereof, or a mixture thereof, or apharmaceutically acceptable salt thereof, a solvate thereof or a prodrugthereof.

In another aspect, the present application is directed to a method forinhibiting growth of tumor cells, comprising contacting the tumor cellswith a therapeutically effective amount of a compound of formula I, astereoisomer thereof, a cis-trans-isomer thereof, a tautomer thereof, ora mixture thereof, or a pharmaceutically acceptable salt thereof, asolvate thereof or a prodrug thereof.

In still another aspect, the present application is directed to a methodfor inhibiting overexpression or mutantion of a receptor tyrosine kinasein a mammal, comprising contacting the receptor tyrosine kinase with atherapeutically effective amount of a compound of formula I, astereoisomer thereof, a cis-trans-isomer thereof, a tautomer thereof, ora mixture thereof, or a pharmaceutically acceptable salt thereof, asolvate thereof or a prodrug thereof.

In still yet another aspect, the present application is directed to amethod for treating and/or preventing physiological abnormity caused byoverexpression or mutation of a receptor tyrosine kinase in a mammal,comprising administering to the mammal in need thereof a therapeuticallyeffective amount of a compound of formula I, a stereoisomer thereof, acis-trans-isomer thereof, a tautomer thereof, or a mixture thereof, or apharmaceutically acceptable salt thereof, a solvate thereof or a prodrugthereof.

DETAILED DESCRIPTION Definitions

Certain chemical groups named herein are preceded by a shorthandnotation indicating the total number of carbon atoms that are to befound in the indicated chemical group. For example, C₇-C₁₂ alkyldescribes an alkyl group, as defined below, having a total of 7 to 12carbon atoms, and C₃-C₁₀ cycloalkyl describes a cycloaklyl group, asdefined below, having a total of 3 to 10 carbon atoms. The total numberof carbon atoms in the shorthand notation does not include the carbonsthat may exist in the substituents of the groups described.

Furthermore, as used in the specification and appended claims of thepresent application, unless specified to the contrary, the followingterms have the meanings indicated:

“Amino” refers to the —NH₂ group. The amino group may be substitutedwith a group selected from alkyl, alkenyl, alkynyl, haloalkyl,haloalkenyl, haloalkynyl, hydroxyalkyl, aralkyl, cycloalkyl,cycloalkylalkyl, and the like.

“Cyano” refers to the —CN group.

“Hydroxy” refers to the —OH group.

“Imino” refers to ═NH substituent.

“Nitro” refers to the —NO₂ group.

“Oxo” refers to ═O substituent.

“Thio” refers to ═S substituent.

“Trifluoromethyl” refers to the —CF₃ group.

“Alkyl” refers to a straight or branched hydrocarbon chain groupconsisting solely of carbon and hydrogen, containing no unsaturation,having from one to twelve carbon atoms, preferably one to eight or oneto six carbon atoms, and which is attached to the rest of the moleculeby a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl(iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl),3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwisespecifically in the specification, an alkyl group may be optionallysubstituted by one or more groups independently selected from the groupconsisting of alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl,cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl, —OR¹⁴,—OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂,—N(R¹⁴)C(O)OR¹⁶, —N(R¹⁴)C(O)R¹⁶, —N(R¹⁴)S(O)_(t)R¹⁶ (wherein t is 1 to2), —S(O)_(t)OR¹⁶ (wherein t is 1 to 2), —S(O)_(t)R¹⁶ (wherein t is 0 to2), and —S(O)_(t)N(R¹⁴)₂ (wherein t is 1 to 2).

In some embodiments, the alkyl group is C₁-C₁₂ alkyl.

In some embodiments, the alkyl group is C₁-C₈ alkyl.

In some embodiments, the alkyl group is C₁-C₆ alkyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain groupconsisting solely of carbon and hydrogen atoms, containing at least onedouble bond, having two to twelve carbon atoms, preferably two to sixcarbon atoms and which is attached to the rest of the molecule by asingle bond, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl,penta-1,4-dienyl, and the like. Unless stated otherwise specifically inthe specification, an alkenyl group may be optionally substituted withone or more groups independently selected from the group consisting ofalkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl,heterocyclyl, heteroaryl, oxo, trimethylsilyl, —OR¹⁴, —OC(O)—R¹⁴,—N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —N(R¹⁴)C(O)OR¹⁶,—N(R¹⁴)C(O)R¹⁶, —N(R¹⁴)S(O)_(t)R¹⁶ (wherein t is 1 to 2), —S(O)_(t)OR¹⁶(wherein t is 1 to 2), —S(O)_(t)R¹⁶ (wherein t is 0 to 2), and—S(O)_(t)N(R¹⁴)₂ (wherein t is 1 to 2).

In some embodiments, the alkenyl group is C₂-C₁₂ alkenyl.

In some embodiments, the alkenyl group is C₂-C₈ alkenyl.

In some embodiments, the alkenyl group is C₂-C₆ alkenyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain groupconsisting solely of carbon and hydrogen atoms, containing at least onetriple bond, having two to twelve carbon atoms, preferably two to sixcarbon atoms and which is attached to the rest of the molecule by asingle bond, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, andthe like. Unless stated otherwise specifically in the specification, analkynyl group may be optionally substituted with one or more groupsindependently selected from the group consisting of alkyl, alkenyl,halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroaralkyl, —OR¹⁴, —OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴,—C(O)N(R¹⁴)₂, —N(R¹⁴)C(O)OR¹⁶, —N(R¹⁴)C(O)R¹⁶, —N(R¹⁴)S(O)_(t)R¹⁶(wherein t is 1 to 2), —S(O)_(t)OR¹⁶ (wherein t is 1 to 2), —S(O)_(t)R¹⁶(wherein t is 0 to 2), and —S(O)_(t)N(R¹⁴)₂ (wherein t is 1 to 2).

In some embodiments, the alkynyl group is C₂-C₁₂ alkynyl.

In some embodiments, the alkynyl group is C₂-C₈ alkynyl.

In some embodiments, the alkynyl group is C₂-C₆ alkynyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain, linking the rest of the molecule of a group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving one to twelve carbon atoms, e.g., methylene, ethylidene,propylidene, n-butylidene, and the like. The alkylene chain is attachedto the rest of the molecule through a single bond and other groupsthrough a single bond. The alkylene chain may be attached to the rest ofthe molecule and to the group through one carbon within the chain orthrough any two carbons within the chain. Unless stated otherwisespecifically in the specification, the alkylidene chain may beoptionally substituted with one or more groups independently selectedfrom the group consisting of alkyl, alkenyl, halo, haloalkenyl, cyano,nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl,—OR¹⁴, —OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂,—N(R¹⁴)C(O)OR¹⁶, —N(R¹⁴)C(O)R¹⁶, —N(R¹⁴)S(O)_(t)R¹⁶ (wherein t is 1 to2), —S(O)_(t)OR¹⁶ (wherein t is 1 to 2), —S(O)_(t)R¹⁶ (wherein t is 0 to2), and —S(O)_(t)N(R¹⁴)₂ (wherein t is 1 to 2).

In some embodiments, the alkylene group is C₁-C₁₂ alkylidene.

In some embodiments, the alkylene group is C₁-C₈ alkylidene.

In some embodiments, the alkylene group is C₁-C₆ alkylidene.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a group,consisting solely of carbon and hydrogen, containing at least one doublebond and having two to twelve carbon atoms, e.g., such as ethenylene,propenylene, n-butenylene, and the like. The alkenylene chain isattached to the rest of the molecule through a single bond and to othergroups through a double bond or a single bond. The points of attachmentsof the alkenylene to the rest of the molecule and to other groups can bethrough one carbon or any two carbons within the chain. Unless statedotherwise specifically in the specification, the alkenylene may beoptionally substituted with one or more groups independently selectedfrom the group consisting of alkyl, alkenyl, halo, haloalkenyl, cyano,nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl,—OR¹⁴, —OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂,—N(R¹⁴)C(O)OR¹⁶, —N(R¹⁴)C(O)R¹⁶, —N(R¹⁴)S (O)_(t)R¹⁶ (wherein t is 1 to2), —S(O)_(t)OR¹⁶ (wherein t is 1 to 2), —S(O)_(t)R¹⁶ (wherein t is 0 to2), and —S(O)_(t)N(R¹⁴)₂ (wherein t is 1 to 2).

In some embodiments, the alkenylene group is C₂-C₁₂ alkenylidene.

In some embodiments, the alkenylene group is C₂-C₈ alkenylidene.

In some embodiments, the alkenylene group is C₂-C₆ alkenylidene.

“Alkoxy” refers to a group of the formula —OR_(a), where R_(a) is analkyl group as defined above. The alkoxy group contains one to twelvecarbon atoms, preferably one to six carbon atoms. The alkyl part of thealkoxy group may be optionally substituted as defined above for for analkyl group.

“Alkoxylalkyl” refers to a group of the formula —R_(a)—O—R_(a), whereeach R_(a) is independently an alkyl group as defined above. The oxygenatom may be bonded to any carbon in either alkyl group. Each alkyl partof the alkoxylalkyl group may be optionally substituted as defined abovefor an alkyl group.

“Aryl” refers to aromatic monocyclic or multicyclic hydrocarbon ringsystem consisting solely of hydrogen and carbon and containing from sixto eighteen carbon atoms, where the ring system may be partiallysaturated. Aryl groups include, but are not limited to the groups suchas phenyl, naphthyl and fluorenyl. Unless stated otherwise specificallyin the specification, the term “aryl” or the prefix “ar-” (such as in“aralkyl”) is meant to include aryl groups optionally substituted withone or more substituents independently selected from the groupconsisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano,nitro, aryl, heteroaryl, heteroaralkyl, —R¹⁵—OR¹⁴, —R¹⁵—OC(O)—R¹⁴,—R¹⁵—N(R¹⁴)₂, —R¹⁵—C(O)R¹⁴, —R¹⁵—C(O)OR¹⁴, —R¹⁵—C(O)N(R¹⁴)₂,—R¹⁵—N(R¹⁴)C(O)OR¹⁶, —R¹⁵—N(R¹⁴)C(O)R¹⁶, —R¹⁵—N(R¹⁴)S (O)_(t)R¹⁶(wherein t is 1 to 2), —R¹⁵—S(O)_(t)OR¹⁶ (wherein t is 1 to 2),—R¹⁵—S(O)_(t)R¹⁶ (wherein t is 0 to 2), and —R¹⁵—S(O)_(t)N(R¹⁴)₂(wherein t is 1 to 2).

In some embodiments, the aryl group is C₆-C₁₈ aryl.

In some embodiments, the aryl group is C₆-C₁₂ aryl.

In some embodiments, the aryl group is C₆-C₁₀ aryl.

“Aralkyl” refers to a group of the formula —R_(a)R_(b), where R_(a) isan alkyl group as defined above and R_(b) is one or more aryl groups asdefined above, e.g., benzyl, diphenylmethyl, and the like. The aryl partmay be optionally substituted as described above.

“Aryloxy” refers to a group of the formula —OR_(b), where R_(b) is anaryl group as defined above. The aryl part of the aryloxy group may beoptionally substituted as defined above.

“Aralkyloxy” refers to a group of the formula —OR_(c), where R_(c) is anaralkyl group as defined above. The aralkyl part of the aralkyloxy groupmay be optionally substituted as defined above.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or multicyclichydrocarbon group consisting solely of carbon and hydrogen atoms,including fused or bridged ring systems and having three to eighteencarbon atoms, preferably three to fifteen carbon atoms, preferably threeto ten carbon atoms, and which is saturated or unsaturated and attatchedto the rest of the molecule by a single bond. The monocyclic groupcomprises, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl. The multicyclic group comprises, e.g.,adamantanyl, norcamphanyl, decalinyl,7,7-dimethyl-biscyclo[2.2.1]heptyl, and the like. Unless statedotherwise specifically in the specification, the term “cycloalkyl” ismeant to include cycloalkyl groups which are optionally substituted withone or more substituents independently selected from the groupconsisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano,nitro, oxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocycylylalkyl, heteroaryl, heteroaralkyl, —R¹⁵—OR¹⁴,—R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂, —R¹⁵—C(O)R¹⁴, —R¹⁵—C(O)OR¹⁴,—R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁶, —R¹⁵—N(R¹⁴)C(O)R¹⁶,—R¹⁵—N(R¹⁴)S(O)_(t)R¹⁶ (wherein t is 1 to 2), —R¹⁵—S(O)_(t)OR¹⁶ (whereint is 1 to 2), —R¹⁵—S(O)_(t)R¹⁶ (wherein t is 0 to 2), and—R¹⁵—S(O)_(t)N(R¹⁴)₂ (wherein t is 1 to 2).

In some embodiments, the cycloalkyl group is C₃-C₁₈ cycloalkyl.

In some embodiments, the cycloalkyl group is C₃-C₁₅ cycloalkyl.

In some embodiments, the cycloalkyl group is C₃-C₁₀ cycloalkyl.

“Cycloalkylalkyl” refers to a group of the formula-R_(a)R_(d), whereR_(a) is an alkyl group as defined above, and R_(d) is a cycloalkylgroup as defined above. The alkyl part and cycloalkyl part may beoptionally substituted as defined above.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl group, as defined above, that issubstituted by one or more halo groups, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like. The alkyl part of thehaloalkyl may be optionally substituted as defined above for an alkylgroup.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringgroup, which contains three to eighteen carbon atoms and one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulphur. Unless stated otherwise specifically in the specification, theheterocyclyl group may be monocyclic, bicyclic, tricyclic or tetracyclicring system, which may include fused or bridged ring systems. Moreover,the nitrogen, carbon or sulphur atom in the heterocyclyl group may beoptionally oxidized, and the nitrogen atom may be optionallyquaternized. The heterocyclyl group may be partially or fully saturated.Examples of such heteroyclyl groups include, but are not limited to,dioxolanyl, thiophene[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl,tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl,thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl.Unless stated otherwise specifically in the specification, the term“heterocyclyl” is meant to include the heterocyclyl groups which may beoptionally substituted with one or more substituents independentlyselected from the group consisting of alkyl, alkenyl, halo, haloalkyl,haloalkenyl, alkoxy, cyano, oxo, thio, nitro, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocycylylalkyl, heteroaryl,heteroaralkyl, —R¹⁵—OR¹⁴, —R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂, —R¹⁵—C(O)R¹⁴,—R¹⁵—C(O)OR¹⁴, —R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁶,—R¹⁵—N(R¹⁴)C(O)R¹⁶, —R¹⁵—N(R¹⁴)S(O)_(t)R¹⁶ (wherein t is 1 to 2),—R¹⁵—S(O)_(t)OR¹⁶ (wherein t is 1 to 2), —R¹⁵—S(O)_(t)R¹⁶ (wherein t is0 to 2), and —R¹⁵—S(O)_(t)N(R¹⁴)₂ (wherein t is 1 to 2).

In some embodiments, the heterocyclyl group is C₃-C₁₈ heterocyclyl.

In some embodiments, the heterocyclyl group is C₃-C₁₂ heterocyclyl.

In some embodiments, the heterocyclyl group is C₃-C₁₀ heterocyclyl.

“Heterocyclylalkyl” refers to a group of the formula-R_(a)R_(e), whereR_(a) is an alkyl group as defined above, and R_(e) is a heterocyclylgroup as defined above. Moreover, if the heterocyclyl is anitrogen-containing heterocyclyl, then the heterocyclyl may be attachedto the alkyl group at the nitrogen atom. The alkyl part of theheterocyclylalkyl group may be optionally substituted as defined abovefor an alkyl group. The heterocyclyl part of the heterocyclylalkyl groupmay be optionally substituted as defined above for a heterocyclyl group.

“Heteroaryl” refers to a 5- to 18-membered aromatic ring group, whichcontains one to seventeen carbon atoms and one to ten heteroatomsselected from the group consisting of nitrogen, oxygen and sulphur. Forthe purpose of the present invention, the heteroaryl group may bemonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems. Moreover, the nitrogen, carbon orsulphur atom in the heteroaryl group may be optionally oxidized, and thenitrogen atom may be optionally quaternized. The examples include, butare not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl,benzoindolyl, benzodioxolanyl, benzofuranyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepanyl,1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxolanyl,benzodioxadienyl, benzopyranyl, benzopyronyl, benzofuranyl,benzofuranonyl, benzothienyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl,dibenzothienyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl,indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl,indolizinyl, isoxazolyl, naphthyl, naphthyridinyl, oxadiazolyl,2-oxoazepinyl, oxazolyl, oxiranyl, 1-phenyl-1H-pyrrolyl, phenazinyl,phenothiazinyl, phenoxazinyl, 2,3-naphthyridinyl, pteridinyl, purinyl,pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,pyrrolyl, quinazolinyl, quinoxalinyl, quinolyl, quinuclidinyl,isoquinolyl, tetrahydroquinolyl, thiazolyl, thiadiazolyl, triazolyl,tetrazolyl, triazinyl and thiophenyl. Unless stated otherwisespecifically in the specification, the term “heteroaryl” is meant toinclude the heteroaryl groups which may be optionally substituted withone or more substituents independently selected from the groupconsisting of alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkenyl,cyano, oxo, thio, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocycylylalkyl, heteroaryl, heteroaralkyl, —R¹⁵—OR¹⁴,—R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂, —R⁵—C(O)R¹⁴, —R¹⁵—C(O)OR⁴,—R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁶, —R¹⁵—N(R¹⁴)C(O)R¹⁶,—R¹⁵—N(R¹⁴)S(O)_(t)R¹⁶ (wherein t is 1 to 2), —R¹⁵—S(O)_(t)OR¹⁶ (whereint is 1 to 2), —R¹⁵—S(O)_(t)R¹⁶ (wherein t is 0 to 2), and—R¹⁵—S(O)_(t)N(R¹⁴)₂ (wherein t is 1 to 2).

In some embodiments, the heteroaryl group is C₅-C₁₈ heteroaryl.

In some embodiments, the heteroaryl group is C₅-C₁₂ heteroaryl.

In some embodiments, the heteroaryl group is C₅-C₁₀ heteroaryl.

“Heteroarylalkyl” refers to a group of the formula —R_(a)R_(f), whereR_(a) is an alkyl group as defined above, and R_(f) is a heteroarylgroup as defined above. The heteroaryl part of the heteroarylalkyl groupmay be optionally substituted as defined above for a heteroaryl group.The alkyl part of the heteroarylalkyl may be optionally substituted asdefined above for an alkyl group.

In definition of groups as described above, each R¹⁴ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl optionallysubstituted with one or more halogens, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroaralkyl; each R¹⁵ isindependently a direct bond or straight or branched alkylene oralkenylene chain; and each R¹⁶ is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteraryl, or heteroaralkyl.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the specificationincludes instances where said event or circumstance occurs and instancesin which it does not. For example, “optionally substituted aryl” meansthat the aryl may or may not be substituted and that the specificationincludes the substituted aryl and the aryl which is not substituted.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficient robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into aneffecacious therapeutic agent.

“Pharmaceutically acceptable salt” includes both acid and base additionsalt.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of free bases,which are not biologically or otherwise undesirable, and which areformed with inorganic acids such as, but not limited to hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid andthe like; and organic acids such as, but not limited to, acetic acid,2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid,aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, camphanic acid, camphor-10-sulfonic acid, capric acid, caproicacid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid,glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid,lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid,malonic acid, mandelic acid, methanesulfonic acid, mucic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, oleinic acid, orotic acid,oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamicacid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid,stearic acid, succinic acid, tartaric acid, thiocyanic acid,p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid and thelike.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base intothe free acid. Salts derived from inorganic bases include, but are notlimited to, sodium, potassium, lithium, ammonium, calcium, magnesium,iron, zinc, copper, manganese, aluminum slats, and the like. Preferredinorganic salts are ammonium, sodium, potassium, calcium, and magnesiumsalts. Salts derived from organic bases include, but are not limited to,slats of primary, secondary and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as ammonia, isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol,2-diethylaminethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, benethamine,benzathine, ethylenediamine, glucosamine, methylglucosamine,theobromine, triethanolamine, trometamol, purine, piperazine,piperidine, N-ethyl piperidine, polyamine resin and the like.Particularly preferred organic bases are isopropylamine, diethylamine,ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

Often crystallization produces a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be hydrate. Alternatively, the solvent may be anorganic solvent. Therefore, the compounds of the present invention mayexist as a hydrate, including monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

An intermediate of a compound of the formula I and all polymorphs andcrystal habits of the foregoing species are also included within thescope of the present invention.

The compounds of the invention or their pharmaceutically acceptablesalts may contain one or more asymmetric centers and may thereforeproduce enantiomers, diastereoisomers and other stereoisomeric forms,that may be defined, in terms of absolute stereochemistry, as (R)- or(S)-, or, as (D)- or (L)-for amino acids. The present invention is meantto include all such possible isomers, as well as their racemic andoptically pure forms. Optically active (+) and (−), (R)- and (S)-, or(D)- and (L)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques, such aschromatography and fractional crystallization. The conventionaltechniques for preparing/isolating a single enantiomer include chiralsynthesis from a suitable optically pure precursor, or resolution of aracemate (or the racemate of a salt or derivative) by using such aschiral High Pressure Liquid Chromatography (HPLC). When the compoundsdescribed herein comprise olefinic double bonds or other centers ofgeometric asymmetry, unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomer”,which refers to two stereoisomers whose molecules are nonsuperimposablemirror image of one another.

A “cis-trans-isomer” refers to a molecule having the molecular formula,in which a spacial configuration of different relative distance betweenthe adjacent atoms or radicals exists due to the factors such as thepresence of a double bond or a ring, which block the free rotation of abond.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

The term “prodrug” is meant to indicate a compound that may be convertedinto a biologically active compound of the invention under physiologicalconditions or by solvolysis. Therefore, the term “prodrug” refers to ametabolic precursor of a compound of the invention that ispharmaceutically acceptable. A prodrug may be inactive whenadministrated to a subject in need thereof, but is converted in vivointo an active compound of the invention. Prodrugs are typically rapidlytransformed in vivo to yield the parent compound of the presentinvention, for example, by hydrolysis in blood. The prodrug compoundoften provides advantages of solubility, tissue compatibility orcontrolled-release in organism of mammals (see Bundgard, H., Design ofProdrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion ofprodrugs is provided in Higuchi, T., et al., “Pro-drugs as NovelDelivery Systems”, A.C.S. Symposium Series, Vol. 14 and BioreversibleCarriers in Drug Design, Ed. Edward B. Roche, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporated infull by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers which release the active compound of the invention in vivo whensuch prodrug is administrated to a mammal subject Prodrugs of a compoundof the invention may be prepared by modifying functional groups presentin the compound of the invention in such a way that the modificationsare cleaved, either in routine manipulation or in vivo, to the parentcompound of the invention. Prodrugs include compounds of the inventionwherein a hydroxy, amino, or mercapto group is bonded to any group that,when the prodrug of the compound of the invention is administered to amammal subject, cleaves to form a free hydroxy, free amino or freemecapto group, respectively. Examples of prodrugs include, but are notlimited to, acetate, formate and benzoate of alcohol functional group inthe compounds of the present invention and the like.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfrom, for example, the oxidization, reduction, hydrolysis, amidation,esterification, and the like of the administered compounds, primarilydue to enzyme processes. Therefore, the invention includes compoundsproduced by a process comprising contacting a compound of the inventionwith a mammal for a period time sufficient to yield a metabolic productthereof. Such products are typically identified by administering aradiolabelled compound of the invention in a detectable dose to ananimal, such as rat, mouse, guinea pig, monkey, or to human, allowingsufficient time to occur, and isolating its conversion products fromurine, blood or other biological samples.

“Mammal” includes humans and both domestic animals, such as laboratoryanimals and household pets (e.g. cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

The term “pharmaceutical composition” refers to a formulation of acompound of the invention and a medium generally acceptable in the artfor the delivery of the biologically active compound to a mammal e.g.humans. Such a medium includes all pharmaceutically acceptable carriersfor use. The pharmaceutical composition is conducive to administrationof a compound to an organism. There are various routes of administrationof a compound in the art including, but not limited to oraladministration, injection administration, aerosol administration,parenteral administration and topical administration. The pharmaceuticalcompositions can also be obtained by reacting a compound with aninorganic acid such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonicacid, p-toluenesulfonic acid, salicylic acid and the like, or with anorganic acid.

The term “carrier” defines a compound that facilitates the incorporationof a compound into cells or tissues. For example, dimethylsulfoxide(DMSO) is generally used as a carrier, as it facilitates the uptake ofmany organic compounds into cells or tissues of an organism.

“Pharmaceutically acceptable carrier” includes without limitation to anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isosmotic agent,solvent, or emulsifier which has been approved by the national drugregulatory authorities as being acceptable for use in humans or domesticanimals.

The term “physiologically acceptable” defines a carrier or a diluentthat does not abrogate the biological activities and properties of acompound.

“Therapeutically effective amount” refers to that amount of a compoundof the invention which, when administered to a mammal, preferably ahuman, is sufficient to effect treatment, as defined below, of the tumorin the mammal, preferably a human. The amount of a compound of theinvention which constitutes a “therapeutically effective amount” willvary depending on the compound, the condition and its severity, theadministration mode and the age of the mammal to be treated, but can bedetermined routinely by one of ordinary skill in the art having regardto his own knowledge and to this disclosure.

“Treating” or “treatment” as used herein covers the treatment of thetumor in a mammal, preferably a human, having the tumor, and includes:

(i) preventing the tumor from occurring in a mammal, in particular, whensuch mammal is predisposed to the tumor but has not yet been diagnosedas having it;

(ii) inhibiting the tumor, i.e. arresting its development; or

(iii) relieving the tumor, i.e. causing regression of the tumor; or

(iv) relieving the symptoms caused by the tumor.

Specific Embodiments

In one aspect, the present application is directed to a compound offormula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof,

wherein:

R¹ is selected from the group consisting of substituted or unsubstitutedalkylacylamino, substituted or unsubstituted alkenylacylamino,substituted or unsubstituted alkynylacylamino, substituted orunsubstituted arylacylamino, substituted or unsubstituted amino, andsubstituted or unsubstituted alkoxy;

R² and R³ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted aralkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl;

or R² and R³ together with nitrogen atom to which they are attached formsubstituted or unsubstituted heterocyclyl; and

R⁴ is substituted or unsubstituted heterocyclyl, or substituted orunsubstituted heteroaryl.

In another aspect, the present application is directed to a compound offormula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof,

wherein:

R¹ is selected from the group consisting of C₁-C₆ alkylacylamino, C₂-C₆alkenylacylamino, C₂-C₆ alkynylacylamino, C₆-C₁₈ arylacylamino, C₁-C₆alkyl-substituted amino, and C₁-C₆ alkoxy;

R² and R³ are each independently selected from the group consisting ofhydrogen, C₇-C₂₄ aralkyl, substituted or unsubstituted C₆-C₁₈ aryl, andsubstituted or unsubstituted C₅-C₁₈ heteroaryl, wherein a substituent onthe aryl is selected from the group consisting of C₂-C₆ alkynyl,halogen, C₇-C₂₄ aralkyloxy, C₆-C₂₄ heteroaralkyloxy, C₆-C₁₈ aryloxy, andC₅-C₁₈ heteroaryloxy, and a substituent on the heteroaryl is selectedfrom the group consisting of C₇-C₂₄ aralkyl, C₆-C₁₈ arylacylamino,C₆-C₁₈ arylsulfonylamino, C₅-C₁₈ heteroarylacylamino, C₃-C₁₀cycloalkylacylamino, C₆-C₁₈ arylaminoacyl, C₇-C₂₄ aralkyloxy, C₆-C₂₄heteroaralkyloxy, and C₆-C₁₈ aryloxy;

or R² and R³ together with nitrogen atom to which they are attached formsubstituted or unsubstituted C₃-C₁₈ heterocyclyl; and

R⁴ is C₃-C₁₈ heterocyclyl or C₅-C₁₈ heteroaryl.

In some embodiments, the present application is directed to a compoundof formula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or prodrug thereof,

wherein:

R¹ is selected from the group consisting of C₁-C₆ alkylacylamino, C₂-C₆alkenylacylamino, C₂-C₆ alkynylacylamino, C₆-C₁₈ arylacylamino, C₁-C₆alkyl-substituted amino, and C₁-C₆ alkoxy;

R² and R³ are each independently selected from the group consisting ofhydrogen, C₇-C₂₄ aralkyl, substituted or unsubstituted C₆-C₁₈ aryl, andsubstituted or unsubstituted C₅-C₁₈ heteroaryl, wherein a substituent onthe aryl is selected from the group consisting of C₂-C₆ alkynyl,halogen, C₇-C₂₄ aralkyloxy, C₆-C₂₄ heteroaralkyloxy, C₆-C₁₈ aryloxy, andC₅-C₁₈ heteroaryloxy, and a substituent on the heteroaryl is selectedfrom the group consisting of C₇-C₂₄ aralkyl, C₆-C₁₈ arylacylamino,C₆-C₁₈ arylsulfonylamino, C₅-C₁₈ heteroarylacylamino, C₃-C₁₀cycloalkylacylamino, C₆-C₁₈ arylaminoacyl, C₇-C₂₄ aralkyloxy, C₆-C₂₄heteroaralkyloxy, and C₆-C₁₈ aryloxy;

or R² and R³ together with nitrogen atom to which they are attached formsubstituted or unsubstituted C₃-C₁₈ heterocyclyl; and

R⁴ is tetrahydrofuranyl.

In some embodiments, the present application is directed to a compoundof formula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof,

wherein:

R¹ is selected from the group consisting of C₁-C₆ alkylacylamino, C₂-C₆alkenylacylamino, C₂-C₆ alkynylacylamino, C₆-C₁₈ arylacylamino, C₁-C₆alkyl-substituted amino, and C₁-C₆ alkoxy;

one of R² and R³ is H, while the other one is selected from the groupconsisting of C₇-C₂₄ aralkyl, substituted or unsubstituted C₆-C₁₈ aryl,and substituted or unsubstituted C₅-C₁₈ heteroaryl, wherein asubstituent on the aryl is selected from the group consisting of C₂-C₆alkynyl, halogen, C₇-C₂₄ aralkyloxy, C₆-C₂₄ heteroaralkyloxy, C₆-C₁₈aryloxy, and C₅-C₁₈ heteroaryloxy, and a substituent on the heteroarylis selected from the group consisting of C₇-C₂₄ aralkyl, C₆-C₁₈arylacylamino, C₆-C₁₈ arylsulfonylamino, C₅-C₁₈ heteroarylacylamino,C₃-C₁₀ cycloalkylacylamino, C₆-C₁₈ arylaminoacyl, C₇-C₂₄ aralkyloxy,C₆-C₂₄ heteroaralkyloxy, and C₆-C₁₈ aryloxy; and

R⁴ is tetrahydrofuranyl.

In some embodiments, the present application is directed to a compoundof formula I, a stereoisomer thereof, a cis-trans isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof,

wherein:

R¹ is selected from the group consisting of C₁-C₆ alkylacylamino, C₂-C₆alkenylacylamino, and C₆-C₁₈ arylacylamino;

one of R² and R³ is H, while the other one is selected from the groupconsisting of C₇-C₂₄ aralkyl, and substituted or unsubstituted C₆-C₁₈aryl, wherein a substituent on the aryl is selected from the groupconsisting of C₂-C₆ alkynyl, halogen, C₇-C₂₄ aralkyloxy, C₆-C₁₈ aryloxy,C₅-C₈ heteroaryloxy, and C₆-C₂₄ heteroaralkyloxy; and

R⁴ is tetrahydrofuranyl.

In some embodiments, the present application is directed to a compoundof formula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof,

wherein:

R¹ is C₂-C₆ alkenylacylamino;

one of R² and R³ is H, while the other one is selected from the groupconsisting of C₇-C₂₄ aralkyl, and substituted or unsubstituted C₆-C₁₈aryl, wherein a substituent on the aryl is selected from the groupconsisting of C₂-C₆ alkynyl, halogen, C₇-C₂₄ aralkyloxy, and C₆-C₂₄heteroaralkyloxy; and

R⁴ is tetrahydrofuranyl.

In some embodiments, the present application is directed to a compoundof formula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof,

wherein:

R¹ is selected from the group consisting of4-(dimethylamino)-but-2-enamido, 4-(diethylamino)-but-2-enamido,4-(piperidin-1-yl)-but-2-enamido, 4-(morpholin-4-yl)-but-2-enamido,4-(tert-butylamino)-but-2-enamido, 4-(benzylamino)-but-2-enamido,4-(6-hydroxyhexylamino)-but-2-enamido,4-(2-methoxylethylamino)-but-2-enamido,2-(piperidin-4-ylidene)acetamido,2-(1-methylpiperidin-4-ylidene)acetamido,4-(diethanolamino)-but-2-enamido, 4-(N-methylmethoxylethylamino)-but-2-enamido, 4-(N-methylethanolamino)-but-2-enamido,4-(dimethoxyl ethyl amino)-but-2-enamido,4-(N-methyl-6-amino-1-hexanolyl)-but-2-enamido,4-(N-methylbenzylamino)-but-2-enamido,2-(1-ethylpiperidin-4-ylidene)acetamido,2-(1-(2-methoxylethyl)piperidin-4-ylidene)acetamido, acrylamido,but-2-enamido, 3-methyl-but-2-enamido, and2-(pyrrolidin-3-ylidene)acetamido;

one of R² and R³ is H, while the other one is selected from the groupconsisting of C₇-C₂₄ aralkyl, and substituted or unsubstituted C₆-C₁₈aryl, wherein a substituent on the aryl is selected from the groupconsisting of C₂-C₆ alkynyl, halogen, C₇-C₂₄ aralkyloxy, and C₆-C₂₄heteroaralkyloxy; and

R⁴ is tetrahydrofuranyl.

In some embodiments, the present application is directed to a compoundof formula I, a stereoisomer thereof, a cis-trans isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof,

wherein:

R¹ is selected from the group consisting of C₁-C₆ alkylacylamino, C₂-C₆alkenylacylamino, and C₆-C₁₈ arylacylamino;

one of R² and R³ is H, while the other one is substituted orunsubstituted C₆-C₁₈ aryl, wherein a substituent on the aryl is selectedfrom the group consisting of halogen, C₆-C₂₄ heteroaralkyloxy, C₂-C₆alkynyl, and C₇-C₂₄ aralkyloxy; and

R⁴ is tetrahydrofuranyl.

In some embodiments, the present application is directed to a compoundof formula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof,

wherein:

R¹ is C₂-C₆ alkenylacylamino;

R² and R³ together with nitrogen atom to which they are attached formsubstituted or unsubstituted C₃-C₁₈ heterocyclyl; and

R⁴ is tetrahydrofuranyl.

In some embodiments, the present application is directed to a compoundof formula I, a stereoisomer thereof, a cis-trans isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof,

wherein:

R¹ is 2-(piperidin-4-ylidene)acetamido;

R² and R³ together with nitrogen atom to which they are attached formsubstituted or unsubstituted C₃-C₁₈ heterocyclyl; and

R⁴ is tetrahydrofuranyl.

In some embodiments, the present application is directed to a compoundof formula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof,

wherein:

R¹ is C₂-C₆ alkenylacylamino;

one of R² and R³ is H, while the other one is selected from the groupconsisting of substituted or unsubstituted C₆-C₁₈ aryl, and substitutedor unsubstituted C₅-C₈ heteroaryl, wherein a substituent on the aryl isselected from the group consisting of C₂-C₆ alkynyl, halogen, C₇-C₂₄aralkyloxy, and C₆-C₁₈ aryloxy, and a substituent on the heteroaryl isselected from the group consisting of C₇-C₂₄ aralkyloxy, and C₆-C₁₈aryloxy; and

R⁴ is hexahydropyridinyl optionally substituted with C₁-C₆ alkyl.

In some embodiments, the present application is directed to a compoundof formula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof, wherein:

R¹ is 2-(piperidin-4-ylidene)acetamido;

one of R² and R³ is H, while the other one is selected from the groupconsisting of substituted or unsubstituted C₆-C₁₈ aryl, and substitutedor unsubstituted C₅-C₁₈ heteroaryl, wherein a substituent on the aryl isselected from the group consisting of C₂-C₆ alkynyl, halogen, C₇-C₂₄aralkyloxy, and C₆-C₁₈ aryloxy, and a substituent on the heteroaryl isC₇-C₂₄ aralkyloxy; and

R⁴ is hexahydropyridinyl optionally substituted with C₁-C₆ alkyl.

In some embodiments, the present application is directed to a compoundof formula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof, wherein:

R¹ is 2-(pyrrolidin-3-ylidene)acetamido;

one of R² and R³ is H, while the other one is C₅-C₈ heteroarylsubstituted with aryloxy; and

R⁴ is hexahydropyridyl optionally substituted with C₁-C₆ alkyl.

In some embodiments, the present application is directed to a compoundof formula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof,

wherein:

R¹ is C₂-C₆ alkenylacylamino;

one of R² and R³ is H, while the other one is selected from the groupconsisting of substituted or unsubstituted C₆-C₁₈ aryl, and substitutedor unsubstituted C₅-C₈ heteroaryl, wherein a substituent on the aryl isselected from the group consisting of C₂-C₆ alkynyl, halogen, C₇-C₂₄aralkyloxy, C₆-C₂₄ heteroaralkyloxy, and C₆-C₁₈ aryloxy, and asubstituent on the heteroaryl is selected from the group consisting ofC₇-C₂₄ aralkyloxy, and C₆-C₁₈ aryloxy; and

R⁴ is pyridinyl.

In some embodiments, the present application is directed to a compoundof formula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof,

wherein:

R¹ is 2-(piperidin-4-ylidene)acetamido;

one of R² and R³ is H, while the other one is selected from the groupconsisting of substituted or unsubstituted C₆-C₁₈ aryl, and substitutedor unsubstituted C₅-C₁₈ heteroaryl, wherein a substituent on the aryl isselected from the group consisting of C₂-C₆ alkynyl, halogen, C₇-C₂₄aralkyloxy, C₆-C₂₄ heteroaralkyloxy, and C₆-C₁₈ aryloxy, and asubstituent on the heteroaryl is selected from the group consisting ofC₇-C₂₄ aralkyloxy, and C₆-C₁₈ aryloxy; and

R⁴ is pyridinyl.

In some embodiments, the present application is directed to a compoundof formula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof, wherein:

R¹ is 2-(pyrrolidin-3-ylidene)acetamido;

one of R² and R³ is H, while the other one is C₅-C₈ heteroarylsubstituted with C₆-C₁₈ aryloxy; and

R⁴ is pyridinyl.

In some embodiments, the present application is directed to a compoundof formula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof, wherein:

R¹ is 4-(diethyl amino)-but-2-enamido;

one of R² and R³ is H, while the other one is C₆-C₁₈ aryl substitutedwith halogen; and

R⁴ is pyridinyl.

The specific embodiments of a compound of formula I are more detailedlydescribed in the following preparations of the compound of the presentinvention.

Methods of Use

The present application provides a method for treating a patient havinga tumor or protecting a patient from development of a tumor, comprisingadministering to an animal in need thereof, such as a mammal, especiallya human patient, a therapeutically effective amount of a compound of thepresent invention or a pharmaceutical composition comprising a compoundof the invention.

The compounds of the invention can be used to treat and/or preventtumor. Therefore, for example, the compounds of the invention can beused to treat, prevent development of a tumor, relieve growth of tumorcells, or kill tumor cells. In some embodiments, the compounds of theinvention are administered to a subject having a tumor. In oneembodiment, the subject is human. In some embodiments, the tumor cellsare contacted with one or more compounds of the invention.

As will be understood by a person having ordinary skill in the art,“need” is not an absolute term and merely implies that the patient canbenefit from the treatment of the anti-tumor agent. By “patient” what ismeant is an organism which benefits by the use of the anti-tumor agent.For example, any organism with the cancer, such as a colorectalcarcinoma, a prostate carcinoma, a breast adenocarcinoma, a non-smallcell lung carcinoma, an ovarian carcinoma, multiple myelomas, amelanoma, and the like, may benefit from the application of theanti-tumor agent that may in turn reduce the amount of the cancerpresent in the patient. In one embodiment, the patient's health may notrequire that an anti-tumor agent be administered, but the patient maystill obtain some benefit by the reduction of the level of the tumorcells present in the patient, and thus be in need. In some embodiment,the anti-tumor agent is effective against one type of the tumor, but notagainst other types, therefore, allowing a high degree of selectivity inthe treatment of the patient. In choosing such an anti-tumor agent, themethods and results disclosed in the examples can be useful.

The term “anti-tumor agent” as used herein refers to a compound orcomposition including the compound that reduces the likelihood ofsurvival of a tumor cell. In one embodiment, the likelihood of survivalis determined as a function of an individual tumor cell. Therefore, theanti-tumor agent will increase the chance that an individual tumor cellwill die. In one embodiment, the likelihood of survival is determined asa function of a polulation of tumor cells. Therefore, the anti-tumoragent will increase the chances that there will be a decrease in thepopulation of tumor cells. In one embodiment, the anti-tumor agent meansthe chemotherapeutant (chemotherapeutic agent) and other similar terms.

The term “chemotherapeutic agent” as used herein refers to a compounduseful in the treatment of the neoplastic disease, such as cancer.Examples of the chemotherapeutic agents include alkylating agent, suchas a nitrogen mustard, an ethyleneimine and a methylmelamine, an alkylsulfonate, a nitrosourea and a triazene, folic acid antagonists,antimetabolites of nucleic acid metabolism, antibiotics, pyrimidineanalogs, 5-fluorouracil, cisplatin, purine nucleosides, amines, aminoacids, triazole nucleosides, corticosteroids, a natural product such asa vinca alkaloid, an epipodophyllotoxin, an antibiotic, an enzyme, ataxane, and a biological response modifier; miscellaneous reagents, suchas a platinum coordination complex, an anthraquinone, an anthracycline,a substituted urea, a methyl hydrazine derivative, or an adrenocorticalsuppressant; or a hormone or an antagonist such as anadrenocorticosteroid, a progesterone, an estrogen, an antiestrogen, anandrogen, an antiandrogen, or a gouadotropin-releasing hormone analog.Specific examples include doxorubicin, 14-hydroxy daunorubicin,5-fluorouracil, cytosine arabinoside (“Ara-C”), cyclophosphamide,thiotepa, busulfan, cytotoxin, taxol, Toxotere, methotrexate, cisplatin,melphalan, vinblastine, bleomycin, etoposide, ifosfamide, mitomycin C,mitoxantrone, vincristine, vinorelbine, carboplatin, teniposide,daunorubicin, 10-demethylated daunorubicin, aminopterin, dactinomycin,mitomycin, esperamicin, melphalan, and other related nitrogen mustards.Also included in this definition are hormone reagents that act toregulate or inhibit hormone action on tumors, such as tamoxifen andonapristone.

The anti-tumor agent may act directly on a tumor cell to kill the cell,induce death of the cell, to prevent division of the cell, and the like.Alternatively, the anti-tumor agent may act indirectly on a tumor cell,such as by limiting nutrient or blood supply to the cell. Suchanti-tumor agents are capable of destroying or suppressing the growth orreproduction of the tumor cells, such as a colon carcinoma, a prostatecarcinoma, a breast adenocarcinoma, a non-small cell lung carcinoma, anovarian carcinoma, multiple myelomas, a melanoma, and the like.

The term “neoplastic disease” or “neoplasm” as used herein refers to acell or a population of cells, including a tumor or tissue (includingcell suspensions such as bone marrow cell and fluids such as blood orserum), that exhibits abnormal growth by cellular proliferation greaterthan normal tissue. Neoplasms can be benign or malignant.

The methods of treatment disclosed herein can be used for any patientsuspectable of having benign or malignant tumor growth, cancer or othertumorigenesis growth (the “tumor” or “tumors” as used herein coverstumor, solid tumor, cancer, disseminated tumor formative cell andtopical tumorigenesis growth). Examples of the growth include, but arenot limited to, breast cancer; osteosarcoma, angiosarcoma, fibrosarcoma,and other sarcoma; leukemia; sinus tumor; cancers of ovarian, ureter,bladder, prostate and other urogenital system; cancers of colon,esophageal and gastric and other gastrointestinal cancer; lung cancer;lymphoma; myeloma; pancreatic cancer; liver cancer; kidney cancer;endocrine cancer; skin cancer; melanoma; hemangioma; and brain orcentral nervous system (CNS; glioma) cancer. Generally, the tumor orgrowth to be treated can be any primary or secondary tumor or cancer.

In some embodiments, the cancer may be, for example, breast cancer,sarcoma, leukemia, ovarian cancer, ureter cancer, bladder cancer,prostate cancer, colon cancer, rectal cancer, stomach cancer, lungcancer, lymphoma, multiple myeloma, pancreatic cancer, liver cancer,kidney cancer, endocrine cancer, skin cancer, melanoma, hemangioma, andbrain or central nervous system (CNS) cancer.

In some aspects, the cancer may be drug-resistant cancer. Thedrug-resistant cancer may exhibit, for example, one of:Bcl-2-overexpression, boosted level of the P-glycoprotein efflux pump,an increased expression of the multidrug-resistance related protein 1encoded by MRP1, reduced drug intakes, the change of the drug target, orincreased repairing of the drug induced DNA damage, the change of theapoptosis pathway, or activation of the cytochrome P450 enzyme. Thedrug-resistant cancer may be, for example, multiple myeloma, sarcoma,lymphoma (including non-Hodgkin's lymphoma), leukemia or any otherdrug-resistant cancer. The cancer may be, for example, naturallydrug-resistant, or resistant to chemotherapy, biological therapy,radiotherapy, or immunotherapy. The cancer may be resistant to rituximabmonoclonal antibody, Gleevac, velcade, Gleveec, Revlimid, Avastin,Tarceva, Erbitux, bortezomib, thalidomide and the like. Other specificexamples of the drug-resistant cell line include MES-SA cell line, andmultidrug-resistant derivative thereof, such as MES-SA/Dx5, HL-60 andHL-60/MX2.

Pharmaceutical Compositions

In one aspect, the present application is directed to a pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundof formula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof, and apharmaceutically acceptable carrier,

wherein:

R¹ is selected from the group consisting of substituted or unsubstitutedalkylacylamino, substituted or unsubstituted alkenylacylamino,substituted or unsubstituted alkynylacylamino, substituted orunsubstituted arylacylamino, substituted or unsubstituted amino, andsubstituted or unsubstituted alkoxy;

R² and R³ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted aralkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl;

or R² and R³ together with nitrogen atom to which they are attached formsubstituted or unsubstituted heterocyclyl; and

R⁴ is substituted or unsubstituted heterocyclyl, or substituted orunsubstituted heteroaryl.

In some embodiments, the pharmaceutical composition of the presentapplication comprises a physiologically acceptable surfactants,carriers, diluents, excipients, smoothing agents, suspending agents,film forming substances, and coating assistants, or a combinationthereof, and a compound of the invention. Acceptable carriers ordiluents for therapeutic use are well-known in the art, and aredescribed, for example, in Remington's Pharmaceutical Sciences, 18thEd., Mack Publishing Co., Easton, Pa. (1990), which is incorporatedherein by reference in its entirety.

Preservatives, stabilizers, dyes, sweeteners, flavoring agents,fragrances, and the like, may be provided in the pharmaceuticalcomposition. For example, sodium benzoate, ascorbic acid and esters ofp-hydroxybenzoic acid may be added as preservatives. Furthermore,antioxidants and suspending agents may be used.

In various embodiments, alcohols, esters, sulfating aliphatic alcohols,and the like may be used as surfactants; sucrose, glucose, lactose,starch, crystalline cellulose, mannitol, light anhydrous silicate,magnesium aluminate, methyl magnesium silicate aluminate, syntheticaluminum silicate, calcium carbonate, calcium bicarbonate, calciumhydrogenphosphate, calcium hydroxymethyl cellulose and the like may beused as excipients; magnesium stearate, talc, hardened oil may be usedas smoothing agents; coconut oil, olive oil, sesame oil, peanut oil,soybean may be used as suspending agents or lubricants; celluloseacetate phthalate as a derivative of a carbohydrate such as cellulose orsugar, or methylacetate-metharylate copolymer as a derivative ofpolyethylene may be used as suspending agents; and plasticizers such asester phthalates and the like may be used as suspending agents.

Suitable routes of administration may, for example, include oral,rectal, transmucosal, topical, or intestinal administration; parenteraldelivery, including intramuscular, subcutaneous, intravenous,intramedullary injections, as well as intrathecal, directintraventricular, intraperitoneal, intranasal or intraocular injections.The compound can be administered in sustained or controlled releasedosage froms, including depot injections, osmotic pumps, pills,transdermal (including electromigrating) patches, and the like forprolonged and/or timed, pulsed administration at a predetermined rate.

Pharmaceutical compositions of the present application may bemanufacture in manner that is itself known, for example, by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping, or tabletting processes.

Pharmaceutical compositions for use in accordance with the presentapplication thus may be formulated by a conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing the active compounds intopreparation which can be used pharmaceutically. Proper formulation isdependent on the route of administration chosen. Any of the well-knowntechniques, carriers and excipients may be used as suitable and asunderstood in the art.

Injectables can be prepared in conventional forms, either as liquidsolutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, glucose, mannitol, lactose,lecithin, albumin, sodium glutamate, cysteine hydrochloride, and thelike. Furthermore, if desired, the injectable pharmaceuticalcompositions may contain minor amounts of nontoxic auxiliary substances,such as wetting agents, pH buffering agents, and the like.Physiologically compatible buffers include, but are not limited to,Hank's solution, Ringer's solution or physiological saline buffer. Ifdesired, absorption enhancing preparations (such as liposomes) may beused.

For transmucosal administration, penetrants suitable for the barrier tobe permeated may be used in the formulation.

Pharmaceutical formulations for parenteral administration, e.g., bybolus injection or continuous infusion, include aqueous solution of theactive compounds in water-soluable form. Furthermore, suspensions of theactive compounds may be prepared as appropriate oily injectionsuspensions. Suitable lipotropic solvents or vehicles include fatty oilsuch as sesame oil, or other organic oils such as soybean oil,grapefruit oil or almond oil, or synthetic fatty acid esters, such asethyl oleate or triglyceride, or liposomes. Aqueous injection suspensionmay contain substances which increase the viscosity of the suspension,such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally,the suspension may also contain suitable stabilizers or agents thatincrease the solubility of the compounds to allow for the preparation ofhighly concentrated solutions. Formations for injection may be presentedin unit dosage form, e.g., in ampoules or in multi-dose containers withan added preservative. The compositions may take such forms assuspensions, solutions or emulsions in oily or aqueous vehicles, and maycontain formulatory agents such as suspending agents, stabilizing and/ordispersing agents. Alternatively, the active ingredient may be in powderform for constitution with a suitable carrier, e.g., sterilepyrogen-free water, before use.

For oral administration, the compound can be formulated readily bycombining the active compound with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compound of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, ointments, suspensions, and the like, for oralingestion by a patient to be treated. Pharmaceutical preparation fororal use can be obtained by combining the active compound with solidexcipient, optionally grinding a resultant mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, saccharose, mannitol orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, hydroxypropyl methylcellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired,disintegrating agents may be added, such as the crosslinkedpolyvinylpyrrolidone, agar, or alginic acid or a salt thereof such assodium alginate. Dragee cores are provided with suitabe coatings. Forthis purpose, concentrated sugar solutions may be used, which mayoptionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solution, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added into the tablets or dagree coatings for identification or tocharacterizing different combinations of active compound doses. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solution, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added into the tablets or dagree coatings for identification or tocharacterizing different combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain active ingredients in admixture with filler such assugar, binders such as starches, and/or lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In soft capsules, theactive ingredients may be dissolved or suspended in suitable liquids,such as fatty oil, liquid paraffin, or liquid polyethylene glycols.Furthermore, stabilizers may be added. All formulations for oraladministration should be in dosages suitable for such administration.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the compound for the invention isconveniently delivered in the form of an aerosol spray presentation fromthe pressurized packs or a nebulizer, with the use of a suitablepropellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, e.g., gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

Further disclosed herein are various pharmaceutical compositions wellknown in the pharmaceutical art for uses that include intraocular,intranasal, and intraauricular delivery. Suitable penetrants for theseuses are generally known in the art. Pharmaceutical compositions forintraocular delivery include aqueous ophthalmic solution of the activecompounds in water-soluble form, such as eyedrops, or in gellan gum orhydrogels; ophthalmic ointments; ophthalmic suspensions, such asmicroparticulates, drug-containing small polymeric particles that aresuspended in a liquid carrier medium, lipid-soluble formulations, andmicrospheres; and ocular inserts. Suitable pharmaceutical formulationsare most often and preferably formulated to be sterile, isotonic andbuffered for stability and comfort. Pharmaceutical compositions forintranasal delivery may also include drops and sprays often prepared tosimulate in many respects nasal secretions to ensure maintenance ofnormal ciliary action. As well known to a person having ordinary skillin the art, suitable formulations are most often and preferablyisotonic, slightly buffered to maintain a pH of 5.5 to 6.5, and mostoften and preferably include antimicrobial preservatives and appropriatedrug stabilizers. Pharmaceutical formulations for intraauriculardelivery include suspensions and ointments for topical application inthe ear. Common solvents for such aural formulations include glycerinand water.

The compound may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., including conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compound mayalso be formulated as a depot preparation. Such long acting formulationsmay be administrated by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Therefore, for example,the compound may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or s sparingly soluble derivatives, for example, as asparingly soluble salt.

For hydrophobic compounds, a suitable pharmaceutical carrier may be acosolvent system comprising benzyl alcohol, a nonpolar surfactant, awater-miscible organic polymer, and an aqueous phase. A common cosolventsystem used is the VPD co-solvent system, which is a solution of 3% w/vbenzyl alcohol, 8% w/v of the nonpolar surfactant POLYSORBATE 80™, and65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.Naturally, the proportions of a co-solvent system may be variedconsiderably without destroying its solubility and toxicity.Furthermore, the identity of the co-solvent may be varied, for example,other low-toxicity nonpolar surfactants may be used instead ofPOLYSORBATE 80™; the fraction size of polyethylene glycol may be varied;other biocompatible polymers may replace polyethylene glycol, e.g.,polyethylene pyrrolidone; and other sugars or polysaccharides maysubstitute for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. Certainorganic solvents such as dimethyl sulfoxide also may be employed,although usually at the cost of greater toxicity. Furthermore, thecompounds may be delivered using a sustained-release system, such assemipermeable matrices of solid hydrophobic polymers containing thetherapeutic agent. Various sustained-release materials have beenestablished and are well known by a person having ordinary skill in theart. Sustained-release capsules may, depending on their chemical nature,release the compound fore a few weeks up to over 100 days.

Agents intended to be administered intracellularly may be administeredusing techniques well known to a person having ordinary skill in theart. For example, such agents may be encapsulated in liposomes. Allmolecules present in an aqueous solution at the time of liposomeformation are incorporated into the aqueous interior. The liposomecontents are both protected from the external micro-environment and,because liposomes fuse with cell membranes, are efficiently deliveredinto the cell cytoplasm. The liposome may be coated with atissue-specific antibody. The liposomes will be targeted to and taken upselectively by the desirable organ. Alternatively, small hydrophobicorganic molecules may be directly administered intracellularly.

Methods of Treatment and Use

In one aspect, the present application is directed to a method fortreating and/or preventing tumor in a mammal, comprising administeringto the mammal in need thereof a therapeutically effective amount of acompound of formula I, a stereoisomer thereof, a cis-trans-isomerthereof, a tautomer thereof, or a mixture thereof, or a pharmaceuticallyacceptable salt thereof, a solvate thereof or a prodrug thereof,

wherein:

R¹ is selected from the group consisting of substituted or unsubstitutedalkylacylamino, substituted or unsubstituted alkenylacylamino,substituted or unsubstituted alkynylacylamino, substituted orunsubstituted arylacylamino, substituted or unsubstituted amino, andsubstituted or unsubstituted alkoxy;

R² and R³ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted aralkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl;

or R² and R³ together with nitrogen atom to which they are attached formsubstituted or unsubstituted heterocyclyl; and

R⁴ is substituted or unsubstituted heterocyclyl, or substituted orunsubstituted heteroaryl.

In some embodiments, the mammal in the method for treating and/orpreventing tumor is a human.

In some embodiment, the receptor tyrosine kinase in the method fortreating and/or preventing tumor in a mammal occurs overexpression ormutation.

In some embodiments, the receptor tyrosine kinase in the method fortreating and/or preventing tumor in a mammal is erbB family.

In some embodiments, the erbB family in the method for treating and/orpreventing tumor in a mammal is selected from EGFR and/or Her2.

In another aspect, the present application is directed to a method forinhibiting growth of tumor cells, comprising contacting the tumor cellswith a therapeutically effective amount of a compound of formula I, astereoisomer thereof, a cis-trans-isomer thereof, a tautomer thereof, ora mixture thereof, or a pharmaceutically acceptable salt thereof, asolvate thereof or a prodrug thereof,

wherein:

R¹ is selected from the group consisting of substituted or unsubstitutedalkylacylamino, substituted or unsubstituted alkenylacylamino,substituted or unsubstituted alkynylacylamino, substituted orunsubstituted arylacylamino, substituted or unsubstituted amino, andsubstituted or unsubstituted alkoxy;

R² and R³ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted aralkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl;

or R² and R³ together with nitrogen atom to which they are attached formsubstituted or unsubstituted heterocyclyl; and

R⁴ is substituted or unsubstituted heterocyclyl, or substituted orunsubstituted heteroaryl.

In some embodiment, the receptor tyrosine kinase in the method forinhibiting growth of tumor cells occurs overexpression or mutation.

In some embodiments, the receptor tyrosine kinase in the method forinhibiting growth of tumor cells is erbB family.

In some embodiments, the erbB family in the method for inhibiting growthof tumor cell is selected from EGFR and/or Her2.

In yet another aspect, the present application is directed to a methodfor inhibiting overexpression or mutantion of a receptor tyrosine kinasein a mammal, comprising contacting the receptor tyrosine kinase with atherapeutically effective amount of a compound of formula I, astereoisomer thereof, a cis-trans-isomer thereof, a tautomer thereof, ora mixture thereof, or a pharmaceutically acceptable salt thereof, asolvate thereof or a prodrug thereof,

wherein:

R¹ is selected from the group consisting of substituted or unsubstitutedalkylacylamino, substituted or unsubstituted alkenylacylamino,substituted or unsubstituted alkynylacylamino, substituted orunsubstituted arylacylamino, substituted or unsubstituted amino, andsubstituted or unsubstituted alkoxy;

R² and R³ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted aralkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl;

or R² and R³ together with nitrogen atom to which they are attached formsubstituted or unsubstituted heterocyclyl; and

R⁴ is substituted or unsubstituted heterocyclyl, or substituted orunsubstituted heteroaryl.

In some embodiments, the receptor tyrosine kinase in the method forinhibiting overexpression or mutation of a receptor tyrosine kinase in amammal is erbB family.

In some embodiments, the erbB family in the method for inhibitingoverexpression or mutation of a receptor tyrosine kinase in a mammal isselected from EGFR and/or Her2.

In yet another aspect, the present application is directed to a methodfor treating and/or preventing physiological abnormity caused byoverexpression or mutation of a receptor tyrosine kinase in a mammal,comprising administering to the mammal in need thereof a therapeuticallyeffective amount of a compound of formula I, a stereoisomer thereof, acis-trans-isomer thereof, a tautomer thereof, or a mixture thereof, or apharmaceutically acceptable salt thereof, a solvate thereof or a prodrugthereof,

wherein:

R¹ is selected from the group consisting of substituted or unsubstitutedalkylacylamino, substituted or unsubstituted alkenylacylamino,substituted or unsubstituted alkynylacylamino, substituted orunsubstituted arylacylamino, substituted or unsubstituted amino, andsubstituted or unsubstituted alkoxy;

R² and R³ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted aralkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl;

or R² and R³ together with nitrogen atom to which they are attached formsubstituted or unsubstituted heterocyclyl; and

R⁴ is substituted or unsubstituted heterocyclyl, or substituted orunsubstituted heteroaryl.

In some embodiments, the receptor tyrosine kinase in the method fortreating and/or preventing physiological abnormity caused byoverexpression or mutation of a receptor tyrosine kinase in a mammal iserbB family.

In some embodiments, the erbB family in the method for treating and/orpreventing physiological abnormity caused by overexpression or mutationof a receptor tyrosine kinase in a mammal is selected from EGFR and/orHer2.

In some embodiments, the physiological abnormity in the method fortreating and/or preventing physiological abnormity caused byoverexpression or mutation of a receptor tyrosine kinase in a mammal istumor.

Methods of Administration

The compound or pharmaceutical compositions may be administered to thepatient in any suitable means. Non-limiting examples of methods ofadministration include, among other, (a) administration through oralpathways, which include administration in capsule, tablet, granule,spray, syrup, or other such forms; (b) administration through non-oralpathways, such as rectal, vaginal, intraurethral, intraocular,intranasal, or intraauricular, which include administration as anaqueous suspension, an oily preparation or the like or as a drip, spray,suppository, salve, ointment or the lise; (c) administration viainjection, subcutaneously, intraperitoneally, intravenously,intramuscularly, intradermally, intraorbitally, intracapsularly,intraspinally, intrasternally, or the like, including infusion pumpdelivery; (d) administration locally such as by injection directly inthe renal or cardiac area, e.g., by depot implantation; as well as (e)administration topically; as deemed appropriate by a person havingordinary skill in the art for bringing the compound of the inventioninto contact with living tissue.

The most suitable route depends on the nature and severity of thecondition to be treated. A person having ordinary skill in the art alsoknows determination of methods of administration (buccal, intravenous,inhalation subcutaneous, rectal and the like), dosage form, suitablepharmaceutical excipients and other events regarding delivering thecompound to a subject in need thereof.

Pharmaceutical compositions suitable for administration include thecompositions where the active ingredient is contained in an effectiveamount to achieve its intended purpose. The therapeutically effectiveamount of the pharmaceutical composition disclosed herein required as adose depends on the route of administration, the type of the animal,including human, being treated, and the physical characteristics of thespecific animal under consideration. The does can be tailored to achievea desired effect, but will depend on such factors as weight, diet,concurrent medication and other factors which those skilled in themedical arts will recognize. More specifically, a therapeuticallyeffective amount means an amount of the compound effective to prevent,alleviate or ameliorate symptoms of disease or prolongs the survival ofthe subject being treated. Determination of a therapeutically effectiveamount is well within the capacity of a person having ordinary skill inthe art, especially in light of the detailed disclosure provided herein.

As will be readily apparent to one skilled in the art, the useful invivo dosage to be administered and particular mode of administrationwill vary depending on the age, weight and f mammal species treated, andthe specific use for which the compound are employed. The determinationof effective amount level, that is, the dosage levels necessary toachieve the desired results, can be accomphlished by a person havingordinary skill in the art using routine pharmacological methods.Typically, human clinical applications of the compound are commenced atlower dosage levels, with dosage level being increased until the desiredeffect is achieved. Alternatively, acceptable in vitro study can be usedto establish useful doses and routes of administration of thecompositions identified by the present methods using establisedpharmacological methods.

In non-human animal studies, applications of potential compounds arecommenced at higher dosage levels, with dosage being decreased until thedesired effect is no longer achieved or the adverse side effectsdisappear. The dosage may range broadly, depending on the desiredeffects and the therapeutic indication. Typically, the dosage may bebetween about 10 μg/kg and 500 mg/kg body weight, preferably betweenabout 100 μg/kg and 200 mg/kg body weight. Alternatively, dosages may bebased and calculated upon the surface area of the patient, as understoodby a person having ordinary skill in the art.

The exact formulation, route of administration and dosage of thepharmaceutical compositions of the invention can be chosed by theindividual physician in view of the patient's condition. Typically, thedose range of the composition administered to the patient can be fromabout 0.5 mg/kg to 1000 mg/kg of the patient's body weight. The dosagemay be a single one or a series of two or more given in the course ofone or more days, as is needed by the patient. In instances where humandosages for compounds have been established for at least some condition,the present invention will use those same dosages, or dosages that arebetween about 0.1% and about 500%, more preferred between 25% to 250% ofthe established human dosage. Where no human dosage is established, aswell be the case for newly-discovered pharmaceutical compounds, asuitable human dosage can be inferred from ED₅₀ or ID₅₀ values, or otherappropriate values derived from in vitro or in vivo studies, asquantified by toxicity studies and efficacy study in animals.

It should be noted that the attending physician would know how to andwhen to terminate, interrupt, or adjust the administration due totoxicity and organs dysfunction. Conversely, the attending physicianwould also know to adjust treatment to higher levels if the clinicalresponse were not adequate (precluding toxicity). The magnitude of anadministered dose in the management of the disorder of interest willvary with the severity of the condition to be treated and to the routeof administration. The severity of the condition may, for example, beevaluated, in part, by standard prognostic evaluation methods. Further,the dose and perhaps dose frequency will also vary according to the age,body weight, and response of the individual patient. A programcomparable to that discussed above may be used in veterinary medicine.

Although the exact dosage will be determined on a drug-by-drug basis, inmost cases, some generalizations regarding the dosage can be made. Thedaily dosage regimen for an adult human patient may be, for example, anoral dose of between 0.1 mg to 2000 mg of each active ingredient,preferably between 1 mg to 1000 mg of each active ingredient, e.g., 5 mgto 500 mg of each active ingredient. In other embodiments, anintravenous, subcutaneous or intramuscular dosage of each activeingredient of between 0.01 mg and 1000 mg, preferably between 0.1 mg and800 mg, e.g. 1 mg to 200 mg is used. In cases of administration of apharmaceutically acceptable salt, dosages may be calculated as the freebase. In some embodiments, the compound is administered one to fourtimes per day. Alternatively, the compositions of the present inventionmay be administered by continuous intravenous infusion, preferably at adose of each active ingredient up to 1000 mg per day. As will beunderstood by a person having ordinary skill in the art, in certainsituations, it may be necessary to administer the compound disclosed inthe present invention in amounts that exceed, or even far exceed, theabove preferred dosage range in order to effectively and aggressivelytreat particularly aggressive diseases or infections. In someembodiments, the compound will be administered for a period ofcontinuous therapy, for example a week or more, or for months or years.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain themodulating effects, or minimal effective concentration (MEC). The MECwill vary for each compound, but the MEC can be estimated from in vitrodata. Dosage necessary to achieve the MEC will depend on individualcharacteristics of route of administration. However, HPLC assays orbiological assay can be used to determine plasma concentrations.

Dosage intervals can be also determined using MEC value. Compositionscan be administered using regimen which maintains plasma levels abovethe MEC for 10-90% of the time, preferably for 30-90% of the time andmore preferably for 50-90% of the time.

In case of local administration or selective uptake, the effective localconcentration of the drug may not be related to plasma concentration.

The amount of the composition administered may be dependent on thesubject being treated, on the subject's weight, the severity of theaffliction, the manner of administration and the judgement of theprescribing physician.

Compounds disclosed in the present application can be evaluated forefficacy and toxicity using known methods. For example, the toxicologyof a particular compound, or of a subset of the compounds, sharingcertain chemical moieties, can be established by determining in vitrotoxicity towards a cell line, such as a mammalian cell line, andpreferably a human cell line. The results of such studies are oftenpredicitive of toxicity in animals, such as mammals, or morespecifically, humans. Alternatively, the toxicity of particularcompounds in an animal model, such as mice, rats, rabbits or monkeys andthe like can be determined using known methods. The efficacy of aparticular compound can be established using several art recognizedmethods, such as in vitro methods, animal models, or human clinicaltrials. Art-recognized in vitro models exist for nearly every class ofcondition, including but not limited to cancer, cardiovascular disease,and various immune dysfunctions. Similarly, acceptable animal models canbe used to establish efficacy of chemicals to treat such conditions.When selecting a model to determine efficacy, the skilled artisan can beguided by the state of the art to choose an appropriate model, dose, androute of administration, and regimen. Of course, human clinical trialscan also be used to determine the efficacy of a compound in humans.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may, for example, comprise metal or plasticfoil, such as a blister pack. The pack or dispenser may be accompaniedwith instructions for administration. The pack or dispenser may be alsoaccompanied with a notice associated with the container in formprescribed by a governmental agency regulating the manufacture, use, orsale of pharmaceuticals, which notice is reflective of approval by theagency of the form of the drug for of human or veterinaryadministration. Such notice, for example, may be the labeling approvedby the United State Food and Drug Administration for prescription drugs,or the approved product insert. Compositions comprising the compound ofthe invention formulated in a compatible pharmaceutical carrier may alsobe prepared, placed in an appropriate container, and labeled fortreatment of an indicated condition.

Preparation of Compounds

The process for preparing a compound of the present invention isexemplarily illustrated in the following reaction scheme. The compoundis a compound of formula I, a stereoisomer thereof, a cis-trans-isomerthereof, a tautomer thereof, or a mixture thereof, or a pharmaceuticallyacceptable salt thereof, a solvate thereof or a prodrug thereof,

wherein R¹, R², R³ and R⁴ are each as defined in the presentapplication.

It is understood that the following description, combinations ofsubstituents and/or the variables of the depicted formulae arepermissible only if such contributions result in stable compounds.

It will also be appreciated by a person having ordinary skill in the artthat in the process described below the functional groups ofintermediate compounds may be needed to be protected by suitableprotecting group. Such functional groups include hydroxy, amino,mercapto and carboxylic acid. Suitable protecting groups for hydroxylinclude trialkylsilyl or diarylalkylsilyl (such astert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl, benzyl, and the like. Suitable protecting groups foramino, amidino and guanidino include tert-butylcarbonyl, carboxybenzyl,fluorenylmethoxy carbony, and the like. Suitable protecting groups formercapto include —C(O)—R″ (where R″ is alkyl, aryl or aralkyl),p-methoxybenzyl, trityl and the like. Suitable protecting groups forcarboxylic acid include alkyl, aryl or aralkyl esters.

Protecting group may be added or removed in accordance with the standardtechniques, which are well-known by a person having ordinary skill inthe art and as described herein.

The use of protecting groups is described in detail in Green, T. W. andP. G. M. Wuts, Protective Groups in Organic Synthesis (1999), 3rd Ed.,Wiley. The protecting group may be polymer resin such as Wang resin or2-chlorotrityl-chloride resin.

It will also appreciated by a person having ordinary skill in the art,although such protected derivatives of compound of this invention maynot possess pharmacological activity as such, they may be administeredto a mammal and thereafter metabolized in the body to form compounds ofthe invention which are pharmacologically active. Such derivatives maytherefore be described as “prodrug”. All prodrugs of compounds of thisinvention are included within the scope of the invention.

The following Reaction Scheme illustrates methods to make compounds ofthis invention. It is understood that a person having ordinary skill inthe art would be able to make these compounds by similar methods or bymethods known to the one skilled in the art. It is also understood thata person having ordinary skill in the art would use suitable startingcomponents in the similar way as described below, and modify thesynthesis parameters as required, in order to manufacture othercompounds of formula I which are not explicitly illustrated hereinafter.In general, starting components may be obtained from the commoncommercial sources or synthesized according to sources known to a personhaving ordinary skill in the art or prepared as described in thisinvention.

R¹, R², R³ and R⁴ are defined in the following reaction scheme as in theSpecification.

In general, the compounds of formula I can be synthesized following thegeneral procedure as described in the Reaction Scheme 1.

In Reaction Scheme 1, R′ represents C₁-C₆ alkylacyl, C₂-C₆ alkenylacyl,C₂-C₆ alkynylacyl, C₆-C₁₈ arylacylamino, or C₁-C₆ alkyl. All thecompounds may be present as a stereoisomer, a cis-trans-isomer, atautomer or a mixture thereof.

As described below, the compound of formula (101) is subject tonitration to obtain the nitrated derivative of formula (102). Nitratingagent may be a mixed acid of nitric acid and sulfuric acid, concentratednitric acid, and preferably a mixed acid. It is well-known for a personhaving ordinary skill in the art how to select conditions of a nitrationreaction.

The compound of formula (102) reacts with alcohol of formula R⁴OH in thepresence of a base. The resulting compound is treated with concentratedsulfuric acid, concentrated hydrochloric acid, concentrated phosphoricacid, and the like, to obtain the compound of formula (103). A base thatcan be used in the present invention includes, but is not limited toLiOH, NaOH, KOH, sodium ethoxide, potassium tert-butoxide, and the like.

The compound of formula (103) reacts with ethyl 2-cyano-3-ethoxyacrylate in a solvent to obtain the compound of formula (104). Thesolvent that can be used in this reaction includes, but is not limitedto dichloromethane, toluene, and the like.

The compound of formula (104) is heated in a solvent in the presence ofinert gas to obtain the compound of formula (105). The solvent that canbe used in this reaction includes, but is not limited to Dowtherm A, andthe like.

The compound of formula (105) reacts with a chlorinating agent to obtainthe compound of formula (106). The chlorinating agent that can be usedin the present invention includes, but is not limited to HCl, SOCl₂,PCl₃, PCl₅, POCl₃, COCl₂, and the like.

The compound of formula (106) reacts with an amine of formula HNR²R³ toobtain the compound of formula (107). The nitro group in the compound offormula (107) is reduced to an amino group with a reduction reaction toobtain the compound of formula (108). The reducing agent that can beused in this reaction includes, but is not limited to hydrogen,Zn/CH₃COOH, SnCl₂, Na₂S_(x), NaSO₃, hydrazine and the like.Alternatively, electrochemical reduction process may be used.

The compound of formula (108) reacts with R′X, in which X represents Cl,Br, F, OMs or OTs to obtain the compound of formula I of the presentinvention.

In the following preparations for preparing intermediates of a compoundof general formula I and the following examples regarding a compound offormula I, the used serial numbers of the compounds do not correspond tothe serial numbers of the compounds described in the above ReactionScheme.

Abbreviations in the following description of the preparation methodsare as follows: Dowtherm A: a mixture of biphenyl and biphenyl ether;DCM: dichloromethane; THF: tetrahydrofuran; DIEA: diisopropylethylamine;DMF: N,N-dimethyl carboxamide; NBS: bromosuccinimide; DMAP:4-dimethylaminopyridine; DCC: dicyclohexylcarbodiimide; Boc:tert-butoxycarbonyl; Fmoc: 9-fluorenylmethoxycarbonyl; Ms:methanesulfonyl; Ts: p-toluene sulfonyl; Su: succinylimide; At:7-azobenzotriazol-1-yl; Bt: benzotriazol-1-yl; CBZ: benzyloxycarbonyl;Tyr: tyrosine; Glu: glutamate.

Unless specifically indicated, all H¹-NMR spectrum measuring instrumentsused in the examples in the present application are 400 MHz nuclearmagnetic resonance spectrometer.

Preparation 1 METHYL 2-ACETYLAMINO-4-FLUORO-5-NITRO-BENZOATE

To a three-neck flask (2,000 ml) was added concentrated nitric acid (500ml). The mixture was cooled in an ice-water bath. Concentrated sulfuricacid (500 ml) was dropwise added to the mixture under mechanicalstirring. After addition, the temperature of the resulting mixture wasmaintained below 15° C. Methyl 2-acetylamino-4-fluoro-benzoate (105.5 g,0.5 mol) was slowly added. The resultant mixture was kept in anice-water bath for 40 min with stirring. Then the mixture was pouredinto ice water (8 L). A large number of yellow solids precipitated. Themixture was stood for 10 min and filtered in vacuo. The filter cake waswashed with lots of water and then transferred in water (2 L). The pH ofthe solution was adjusted to 7 with ammonia liquor under stirring andfiltered in vacuo. The filter cake was dried by baking and recrystalizedwith ethyl acetate.

Preparation 2 4-NITRO-3-(TETRAHYDROFURAN-3-YL-OXY)-BENZENAMINE

To a single-neck reaction flask (100 ml) was added3-hydroxytetrahydrofuran (27 ml, 400 mmol) under argon atmosphere. Tothe flask was added potassium tert-butoxide (15.9 g, 150 mmol) in batchunder stirring. The resulting mixture was warmed to the temperature of75° C. and stirred. After 15 min, the white solid substantiallydisappeared. Methyl 2-acetylamino-4-fluoro-5-nitro-benzoate (25.6 g, 100mmol) was slowly added in batch to the solution. After addition, theresultant mixture was heated and stirred for further 50 min. Thereaction was stopped. The mixture was slightly cooled and poured intowater (500 ml). A large number of red solids precipitated. The pH of thesolution was adjusted to 3 with hydrochloric acid (2N). The solidsbecame yellow. The solution was extracted with ethyl acetate three times(total 800 mL). The aqueous layer was discarded. The layers of ethylacetate were combined and washed once with water (300 mL) and once withsaturated NaCl solution (300 mL). The organic layer was dried over MgSO₄for half-hour, filtered and rotary-evaporated to dryness. The resultantsubstance was dried with an oil pump to give a tawny foam.

Concentrated sulfuric acid (200 mL) was dropwise added into water (300mL) in an ice-water bath. The resultant acid was poured into the tawnyfoam. The mixture was stirred for 4.5 h in an oil bath at thetemperature of 110° C. The reaction was stopped. The reaction solutionwas poured into ice water (2 L). The mixture was stirred in an ice waterbath. The pH of the resulting solution was adjusted to 9 with ammonialiquor. The resultant mixture was extracted with ethyl acetate threetimes. The ethyl acetate layers were combined and washed with water (500mL), saturated NaHCO₃ solution (500 mL), and saturated NaCl solution(500 mL), successively. The resultant organic layer was dried over MgSO₄for half-hour. The mixture was filtered and rotary-evaporated todryness. The resultant substance was purified with column chromatography(eluent: dichloromethane:ethyl acetate=2:5) to give a yellow solid.Yield: 11.5 g, 51%.

Preparation 3 (E/Z)-ETHYL2-CYANO-3-(4-NITRO-3-(TETRAHYDROFURAN-3-YL-OXY)-PHENYLAMINO)-ACRYLATE

To a single-neck reaction flask (250 mL) were added4-nitro-3-(tetrahydrofuran-3-yl-oxy)-benzenamine (7.966 g, 35.722 mmol),(E/Z)-ethyl 2-cyano-3-ethoxy acrylate (8.452 g, 50.0 mmol) and toluene(146 mL). The mixture was stirred and refluxed for 16 hr in an oil bathat the temperature of 115° C. The reaction was stopped. The resultantmixture was cooled in an ice-water bath and filtered in vacuo. Thefilter cake was washed with mother liquor, toluene (200 mL) andanhydrous ethyl ether, successively. The filter cake was pumped todryness to give a yellow solid (11.5 g). The resultant substance wasrecrystalized with ethylene glycol monomethyl ether to give a yellowcrystal (9.95 g). Yield: 80.5%.

Preparation 4a4-HYDROXY-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

To a three-neck flask (2000 mL) under argon atmosphere was added(E/Z)-ethyl2-cyano-3-(4-nitro-3-(tetrahydrofuran-3-yl-oxy)phenylamino)-acrylate(17.09 g, 49.251 mmol). To the flask was added Dowtherm A (600 mL) underargon atmosphere. After 10 min, the mixture was heated. The mixture wasstirred at the temperature of about 256° C. for 2 hr. The resultantmixture was stood to cool to the room temperature. Yellow solidsprecipitated. Anhydrous ethyl ether (360 mL) was added to the mixture.The resulting mixture was stirred for 15 min at the room temperature andfiltered in vacuo. The filter cake was washed with anhydrous ethyl etherand dried in the air. The fiter cake was dissolved in THF (40 mL). Thesolution was stirred and refluxed at the temperature of 85° C. for 1 hr,cooled to the room temperature and filtered in vacuo. The resultantfilter cake was washed with mother liquor and dried in the air. Theresultant substance was recrystalized with ethylene glycol monomethylether to give a gray solid (6.485 g). Yield: 43.7%.

Preparation 4b 7-FLUORO-4-HYDROXY-6-NITROQUINOLINE-3-CARBONITRILE

The titled compound was prepared with 3-fluoro-4-nitrobenzenamine asstarting material according to the processes of the Preparation 3 andPreparation 4a.

Preparation 4c(S)-4-HYDROXY-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

The titled compound was prepared with(S)-4-hydroxy-6-nitro-7-(tetrahydrofuran-3-yl-oxy)quinoline-3-carbonitrileas starting material according to the processes of the Preparation 3 andPreparation 4a.

Preparation 4d(R)-4-HYDROXY-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

The titled compound was prepared with(R)-4-hydroxy-6-nitro-7-(tetrahydrofuran-3-yl-oxy)quinoline-3-carbonitrileas starting material according to the processes of the Preparation 3 andPreparation 4a.

Preparation 5a4-CHLORO-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

To a single-neck reaction flask (100 ml) were added4-hydroxy-6-nitro-7-(tetrahydrofuran-3-yl-oxy)quinoline-3-carbonitrile(1.8 g, 3 mmol) and POCl₃ (10 mL) under argon atmosphere. The mixturewas warmed to the temperature of 105° C. The reaction mixture wasstirred for 2.5 hr. Then the reaction was stopped. The resultant mixturewas rotary-evaporated to dryness. DCM (20 mL) was added to dissolve theresultant mixture. The solution was poured into a cooled mixturesolution of DCM (200 mL) and saturated K₂CO₃ solution (60 mL). Theresultant mixture was stirred for 10 min. The solution was extracted andthe aqueous layer was discarded. The DCM layer was washed with water(150 mL) and staturated NaCl solution (150 mL), successively. Theresultant substance was dried over MgSO₄ for half-hour, filtered,rotary-evaporated to dryness, and dried in vacuo to give a yellow solid(1.771 g). Yield: 92.7%.

The compounds of Preparation 5b and Preparation 5c were prepared withthe compounds obtained from Preparation 4c and Preparation 4d asstarting materials, respectively, according to the process ofPreparation 5a.

Preparation 5b(S)-4-CHLORO-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 5c(R)-4-CHLORO-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 6a 3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)BENZENAMINE

To a reaction flask were added 2-chloro-4-tert-butylcarbonylamino-phenol(24.35 g, 100 mmol), 2-chloromethylpyridine hydrochloride (32.8 g, 200mmol), potassium carbonate (41.4 g, 300 mmol) and tetrabutyl amimoniumiodide (1.107 g, 3 mmol). To the flask was added DMF (100 ml). Thereaction mixture was stirred. After the reaction finished, the reactionsolution was poured into water (1 L). The mixture was extracted withethyl acetate three times. The ethyl acetate layers were combined. Theresultant organic layer was washed with water (500 ml) and staturatedsaline solution (500 ml), successively. The resulting mixture was driedover anhydrous magnesium sulfate for 30 min, filtered androtary-evaporated to dryness. The resultant substance was purified withcolumn chromatography (eluent: ethyl acetate:petroleum ether=1:) to giveN-(3-chloro-4-(pyridin-2-yl-methoxy)phenyl)-tert-butoxyacylamine.

To a reaction flask was added N-(3-chloro-4-(pyridin-2-yl-methoxy)phenyl)-tert-butoxyacylamine.N-(3-chloro-4-(pyridin-2-yl-methoxy)phenyl)-tert-butoxy acylamine wasdissolved with 20% TFA in DCM (50 ml). The mixture was stirred at theroom temperature. After the reaction finished, the solvent wasrotary-evaporated. The residue was dissolved in DCM (200 ml). Theresulting solution was washed with saturated sodium carbonate threetimes (200 ml×3), with water (200 ml) once, with saturated salinesolution (200 ml) once, successively. The resultant substance was driedover anhydrous magnesium sulfate and filtered. The solvent wasrotary-evaporated to give the target product.

The compounds of Preparations 6b to Preparation 6g were prepared withdifferent starting materials according to a process similar to that ofPreparation 6a.

Preparation 6b 1-BENZYL-1H-INDOLE-5-AMINE

Preparation 6c 3-((5-AMINO-1H-INDOL-1-YL)METHYL)BENZONITRILE

Preparation 6d 1-(3-METHOXYBENZYL)-1H-INDOL-5-AMINE

Preparation 6e 1-(3-CHLOROBENZYL)-1H-INDOL-5-AMINE

Preparation 6f 6-(BENZYLOXY)-INDOLINE

Preparation 6g 6-(BENZYLOXY)PYRIDIN-3-AMINE

Preparation 6h 4-(2-CHLOROBENZYLOXY)-3-CHLOROBENZENAMINE

To a reaction flask were added 2-chloro-4-nitrophenol (5.205 g, 30mmol), 2-chlorobenzyl chloride (5.313 g, 33 mmol), potassium carbonate(4.554 g, 33 mmol) and DMF (40 ml). The reaction mixture was heated tothe temperature of 100° C. After the reaction finished, the reactionsolution was poured into water (400 ml). The mixture was extracted withethyl acetate (300 ml). The ethyl acetate layer was washed withsaturated saline solution (200 ml) once and dried over anhydrousmagnesium sulfate. The organic layer was filtered and the solvent wasrotary-evaporated to dryness. The resultant substance was recrystalizedwith ethyl acetate to give 1-(2-chlorobenzyloxy)-2-chloro-4-nitrobenzene(8.567 g).

To a three-neck flask (500 ml) was added1-(2-chlorobenzyloxy)-2-chloro-4-nitrobenzene (8.567 g). To the flaskwere added THF (100 ml) and methanol (50 ml). The solution wasmechanically stirred and heated under reflux. Glacial acetic acid (17ml) and reduced iron powders (16.8 g) were added into the solution. Themixture reacted for 1 hr. After the reaction finished, the resultantsubstance was filtered in vacuo and the filtrate was rotary-evaporatedto dryness. To the resultant crude product was added HCl (4N, 200 ml).The mixture was sufficiently vibrated and then filtered in vacuo. To theresultant filter cake was added water (100 ml). The pH of the mixturewas adjusted to 12 with 5% sodium hydroxide. Ethyl acetate (700 ml) wasadded. The solution was sufficiently vibrated and separated. The ethylacetate layer was washed with saturated sodium carbonate (200 ml), water(200 ml) and staturated saline solution (200 ml), successively. Theorganic layer was dried over anhydrous magnesium sulfate and filtered.The solvent was rotary-evaporated to dryness. The resultant substancewas recrystalized with ethyl acetate to give the target compound.

The compounds of Preparation 6i to Preparation 6aa were preparedaccording to the process of Preparation 6h.

Preparation 6i 4-(2-FLUOROBENZYLOXY)-3-CHLOROBENZENAMINE

Preparation 6j 4-(3-FLUOROBENZYLOXY)-3-CHLOROBENZENAMINE

Preparation 6k 4-(4-FLUOROBENZYLOXY)-3-CHLOROBENZENAMINE

Preparation 6l 4-(3-CHLOROBENZYLOXY)-3-CHLOROBENZENAMINE

Preparation 6m 4-(4-CHLOROBENZYLOXY)-3-CHLOROBENZENAMINE

Preparation 6n 4-(2-METHYLBENZYLOXY)-3-CHLOROBENZENAMINE

Preparation 6o 4-(3-METHYLBENZYLOXY)-3-CHLOROBENZENAMINE

Preparation 6p 4-(4-METHYLBENZYLOXY)-3-CHLOROBENZENAMINE

Preparation 6q 4-(2-METHOXYBENZYLOXY)-3-CHLOROBENZENAMINE

Preparation 6r 4-(3-METHOXYBENZYLOXY)-3-CHLOROBENZENAMINE

Preparation 6s 4-(4-METHOXYLBENZYLOXY)-3-CHLOROBENZENAMINE

Preparation 6t 2-((4-AMINO-2-CHLOROPHENOXY)METHYL)BENZONITRILE

Preparation 6u 3-((4-AMINO-2-CHLOROPHENOXY)METHYL)BENZONITRILE

Preparation 6v 4-((4-AMINO-2-CHLOROPHENOXY)METHYL)BENZONITRLE

Preparation 6w 4-(4-TERT-BUTYLBENZYLOXY)-3-CHLOROBENZENAMINE

Preparation 6x 4-(BENZYLOXY)-3-CHLOROBENZENAMINE

Preparation 6y 4-(2-CHLOROBENZYLOXY)-3-FLUOROBENZENAMINE

Preparation 6z 4-(3-CHLOROBENZYLOXY)-3-FLUOROBENZENAMINE

Preparation 6aa 4-(4-CHLOROBENZYLOXY)-3-FLUOROBENZENAMINE

Preparation 6ab 4-(4-BROMOBENZYLOXY)-3-CHLOROBENZENAMINE

Preparation 6ac 4-(4-ETHYLBENZYLOXY)-3-CHLOROBENZENAMINE

Preparation 6ad 4-(4-ETHOXYBENZYLOXY)-3-CHLOROBENZENAMINE

Preparation 6ah 6-(3-CHLOROBENZYLOXY)PYRIDINE-3-AMINE

Preparation 6ai 4-(3-METHOXYBENZYLOXY)BENZENAMINE

Preparation 6aj 4-BENZYLOXYBENZENAMINE

Preparation 6ak 2-AMINO-5-(N-BENZOYL)-AMINO-PYRIMIDINe

To a three-neck flask were added 2-amino-5-nitropyrimidine (1.4 g, 10mmol), (Boc)₂O (2.18 g, 10 mmol), sodium bicarbonate (1.4 g), THF (15ml) and water (15 ml). The mixture was stirred at the room temperaturefor 4 hr. After the reaction finished, the resultant mixture was exactedwith chloroform three times (20 ml*3). The organic phases were combinedand washed once with saturated sodium chloride solution (20 ml). Theorganic phase was dried over anhydrous magnesium sulfate. Afterhalf-hour, the drying agent was discarded and the filtrate wasconcentrated in vacuo to give5-nitro-2-(N-tert-butoxycarbonyl)-aminopyrimidine as a solid (2.3 g).

5-nitro-2-(N-tert-butoxycarbonyl)-aminopyrimidine (2.3 g) was dissolvedin THF solution (20 ml). 10% palladium on carbon (230 mg) was added tothe solution. The mixture was hydrogenated for 6 hr. The solution wasfiltered with silica gel-sand panel funnel. The filtrate was retainedand the solvent was evaporated in vacuo. The resultant substance waspurified by flash chromatography with silica gel column and eluated withchloroform:methanol=9:1 to give5-amino-2-(N-tert-butoxycarbonyl)-aminopyrimidine (1.5 g).

5-amino-2-(N-tert-butoxycarbonyl)-aminopyrimidine (1.5 g) was dissolvedin redistilled DCM (15 ml). Redistilled triethylamine (1.2 ml, 8.6 mmol)was added. The solution was cooled in an ice water bath under nitrogenatmosphere. After 20 min, a solution of benzoyl chloride (1 ml) in DCM(5 ml) was dropwise added into the solution. The ice water bath wasremoved after the addition finished. The solution was stirred overnight.To the solution was added water (100 ml). The resultant solution wasextracted and separated. The organic phase was retained and washed oncewith of saturated sodium chloride (20 ml) and dried over anhydrousmagnesium sulfate. After 0.5 hr, the solution was filtered. The filtratewas concentrated in vacuo. The resulting substance was purified by flashchromatography with silica gel column and eluated withchloroform:methanol=95:5 to give2-(N-tert-butoxycarbonyl)-amino-5-(N-benzoyl)-aminopyrimidine (1.6 g).

2-(N-tert-butoxycarbonyl)-amino-5-(N-benzoyl)-aminopyrimidine (1.6 g)was dissolved in DCM (20 ml). Trifluoroacetic acid (1.5 ml, 5.8 mmol)was added under stirring at the room temperature. The mixture wasstirred at the room temperature. After 2 hr, the reaction was stopped.The solvent was rotary-evaporated to dryness in vacuo. To the resultantsubstance was added ethyl acetate (20 ml) and 2N HCl (20 ml). Themixture was extracted and separated. The aqueous phase was retained andthe pH was adjusted to 10 with 10% sodium hydroxide solution. Theresulting mixture was extracted three times with ethyl acetate (25 ml*3)and the ethyl acetate layers were combined. The resultant organic phasewas washed with saturated sodium chloride (20 ml) once and dried overanhydrous magnesium sulfate. After 0.5 hr, the solution was filtered andthe filtrate was concentrated in vacuo to give2-amino-5-(N-benzoyl)-amino-pyrimidine (0.7 g).

The compounds of Preparation 6al to Preparation 6an were preparedaccording to the process of Preparation 6ak.

Preparation 6al 2-AMINO-5-(N-4-DIMETHYLAMINO-BENZOYL)-AMINO-PYRIMIDINE

Preparation 6am 2-AMINO-5-(N-4-METHOXY-BENZOYL)-AMINO-PYRIMIDINE

Preparation 6an 2-AMINO-5-(N-BENZENESULFONYL)-AMINO-PYRIMIDINE

Preparation 6ao 2-(N-BENZOYL)-AMINO-5-AMINO-PYRIMIDINE

To stirred solution of 2-amino-5-nitropyrimidine (1.0 g, 7.14 mmol) inpyridine (20 ml) was added benzoyl chloride (0.92 ml, 7.93 mmol). Themixture was refluxed for 4 hr under nitrogen atmosphere. The reactantmixture was cooled to the room temperature and poured into 200 ml water.The resulting mixture was stirred overnight and then filtered in vacuo.The filter cake was washed with water (20 ml*3) and dried in vacuo togive 2-(N-benzoyl)amino-5-nitropyrimidine as a white solid (790 mg).

2-(N-benzoyl)amino-5-nitropyrimidine (790 mg) was added into ethanol(100 ml). 80 mg of 10% palladium on carbon was added to the solutionunder stirring at the room temperature. The reactant was hydrogenatedand stirred for 4 hr. The solution was filtered through silica gel-sandpanel funnel. The filtrate was retained and the solvent was evaporatedin vacuo. The resultant substance was purified by flash chromatographywith silica gel column and eluated with chloroform:methanol=95:5 to give2-(N-benzoyl)amino-5-aminopyrimidine (200 mg).

The compounds of Preparation 6ap to Preparation 6as were preparedaccording to the process of Preparation 6ao.

Preparation 6ap 2-(N-4-METHOXY-BENZOYL)-AMINO-5-AMINO-PYRIMIDINE

Preparation 6aq 2-(N-CYCLOHEXYL-1-BENZOYL)-AMINO-5-AMINO-PYRIMIDINE

Preparation 6ar 2-(N-2-FORMYL-THIOPHENYL)-AMINO-5-AMINO-PYRIMIDINE

Preparation 6as 2-(N-2-FORMYL-FURANYL)-AMINO-5-AMINO-PYRIMIDINE

Preparation 7a4-(3-CHLORO-4(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

To a single-neck reaction flask (500 ml) were added4-chloro-6-nitro-7-(tetrahydrofuran-3-yl-oxy)quinoline-3-carbonitrile (5g, 15.649 mmol), 3-chloro-4-(pyridin-2-yl-methoxy)benzenamine (4.037 g,17.214 mmol) and pyridine hydrochloride (421 mg). To the flask was addedisopropanol (150 ml). The mixture was stirred and refluxed for 2 hr atthe temperature of 85° C. The reaction was stopped and cooled to theroom temperature. The resultant mixture was filtered in vacuo. Thefilter cake was washed with mother liquor and dried in vacuo to give ayellow solid (5.988 g). Yield: 73.9%.

The compounds of Preparation 7b to Preparation 7bh were prepared withdifferent starting materials according to the process of Preparation 7a.

Preparation 7b4-(3-CHLORO-4-FLUOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7c4-(3-ALKYNYLPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7d4-(3-BROMOPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7e6-NITRO-4-(1H-INDOL-5-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7f4-(4-(2-FLUOROBENZYLOXY)-3-FHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7g4-(4-(3-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7h4-(4-(4-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7i4-(4-(2-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7j4-(4-(3-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7k4-(4-(4-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7l4-(4-(2-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7m4-(4-(3-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7n4-(4-(4-NETHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7o4-(4-(2-METHOXYBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7p4-(4-(3-METHOXYBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7q4-(4-(4-METHOXYBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7r4-(4-(2-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7s4-(4-(3-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7t4-(4-(4-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7u4-(4-(4-TERT-BUTYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7v4-(4-BENZYLOXY-3-CHLOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7x4-(4-(2-CHLOROBENZYLOXY)-3-FLUOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7y4-(4-(3-CHLOROBENZYLOXY)-3-FLUOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7z4-(4-(4-CHLOROBENZYLOXY)-3-FLUOROPHENYLAMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7aa6-NITRO-4-((S)-1-PHENYLETHYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7ab6-NITRO-4-((R)-1-PHENYLETHYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7ac4-(1-BENZYL-1H-INDOL-5-YLAMINE)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7ad4-(1-(3-CYANOBENZYL)-1H-INDOL-5-YL-AMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7ae4-(1-(3-METHOXYBENZYL)-1H-INDOL-5-YL-AMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7af4-(1-(3-CHLOROBENZYL)-1H-INDOL-5-YL-AMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7ag4-(INDOLIN-1-YL)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7ah4-(6-CHLOROINDOLIN-1-YL)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7ai4-(6-FLUOROINDOLIN-1-YL)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7aj4-(4-CHLOROINDOLIN-1-YL)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7ak 4-(3,4-DIHYDROQUINOLIN-1(2H)-YL)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7al 4-(6-METHYL-3,4-DIHYDROQUINOLIN-1(2H)-YL)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7am6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)-4-(7-(TRIFLUOROMETHYL)-3,4-DIHYDROQUINOLIN-1(2H)-YL)QUINOLINE-3-CARBONITRILE

Preparation 7an4-(6-(BENZYLOXY)INDOLIN-1-YL)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7ao Methyl1-(3-CYANO-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4YL)INDOLINE-2-CARBOXYLATE

Preparation 7ap4-(2-(HYDROXYMETHYL)INDOLIN-1-YL)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7aq4-(6-(1H-PYRROL-1-YL)INDOLIN-1-YL)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7ar6-NITRO-4-(OCTAHYDROINDOL-1-YL)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7as6-NITRO-4-(PYRIMIDIN-2-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7atN-(2-(3-CYANO-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-5-YL)BENZAMIDE

Preparation 7auN-(2-(3-CYANO-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-5-YL)-4-(DIMETHYLAMINO)BENZAMIDE

Preparation 7avN-(2-(3-CYANO-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-5-YL)BENZENESULFONAMIDE

Preparation 7awN-(5-(3-CYANO-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN4-4-YL-AMINO)PYRIMIDIN-2-YL)BENZAMIDE

Preparation 7axN-(5-(3-CYANO-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN4-4-YL-AMINO)PYRIMIDIN-2-YL)FURAN-2-CARBOXAMIDE

Preparation 7ayN-(5-(3-CYANO-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN4-4-YL-AMINO)PYRIMIDIN-2-YL)THIOPHENE-2-CARBOXAMIDE

Preparation 7azN-(5-(3-CYANO-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-2-YL)CYCLOHEXYLCARBOXAMIDE

Preparation 7ba5-(3-CYANO-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)-N-(4-METHOXYPHENYL)PYRIMIDINE-2-CARBOXAMIDE

Preparation 7bb6-NITRO-4-(PYRIDIN-2-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7bc6-(3-CYANO-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)-N-(4-METHOXYPHENYL)NICOTINAMIDE

Preparation 7bd6-NITRO-4-(PYRIDIN-3-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7be6-NITRO-4-(PYRIDIN-4-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7bf4-(6-(BENZYLOXY)PYRIDIN-3-YL-AMINO)-6-NITRO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7bg6-NITRO-4-(PYRAZIN-2-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7bh4-(3-CHLORO-4-FLUOROPHENYLAMINO)-7-FLUORO-6-NITROQUINOLINE-3-CARBONITRILE

Preparation 7bi4-(3-CHLORO-4-FLUOROPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITROQUINOLINE-3-CARBONITRILE

The compound was obtained according to the process of Preparation 2 with4-(3-chloro-4-fluorophenylamino)-7-fluoro-6-nitroquinoline-3-carbonitrileand 4-hydroxy-1-methylpiperidine as starting materials.

The compounds of Preparation 7bj to Preparation 7by were preparedaccording to the process of Preparation 7bi.

Preparation 7bj4-(3-ETHYNYLPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITROQUINOLINE-3-CARBONITRILE

Preparation 7bk4-(4-BENZYLOXY-3-CHLOROPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITROQUINOLINE-3-CARBONITRILE

Preparation 7bl4-(4-(2-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITROQUINOLINE-3-CARBONITRILE

Preparation 7bm4-(4-(3-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITROQUINOLINE-3-CARBONITRILE

Preparation 7bn4-(4-(4-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITROQUINOLINE-3-CARBONITRILE

Preparation 7bo4-(4-(4-BROMOBENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITROQUINOLINE-3-CARBONITRILE

Preparation 7bp4-(4-(4-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITROQUINOLINE-3-CARBONITRILE

Preparation 7bq4-(4-(4-METHOXYBENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITROQUINOLINE-3-CARBONITRILE

Preparation 7br4-(4-(4-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITROQUINOLINE-3-CARBONITRILE

Preparation 7bs4-(4-(4-ETHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITROQUINOLINE-3-CARBONITRILE

Preparation 7bt4-(4-(4-ETHOXYBENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITROQUINOLINE-3-CARBONITRILE

Preparation 7bu4-(3-CHLORO-4-PHENOXYPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITROQUINOLINE-3-CARBONITRILE

Preparation 7bv7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITRO-4-(PYRIDIN-2-YL-AMINO)QUINOLINE-3-CARBONITRILE

Preparation 7bw7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITRO-4-(PYRIDIN-3-YL-AMINO)QUINOLINE-3-CARBONITRILE

Preparation 7bx7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITRO-4-(PYRIDIN-4-YL-AMINO)QUINOLINE-3-CARBONITRILE

Preparation 7by4-(6-(BENZYLOXY)PYRIDIN-3-YL-AMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)-6-NITROQUINOLINE-3-CARBONITRILE

Preparation 7bz4-(3-CHLORO-4-FLUOROPHENYLAMINO)-6-NITRO-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

The compound was prepared according to the process of Preparation 2 andwith4-(3-chloro-4-fluorophenylamino)-7-fluoro-6-nitroquinoline-3-carbonitrileand 4-hydroxypyridine as starting materials.

The compounds of Preparation 7ca to Preparation 7cl were preparedaccording to the process of Preparation 7bz.

Preparation 7ca4-(3-ETHYNYLPHENYLAMINO)-6-NITRO-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7cb6-NITRO-4-(4-PHENOXYPHENYLAMINO)-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7cc4-(4-(BENZYLOXY)PHENYLAMINO)-6-NITRO-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7cd4-(4-(2-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7ce4-(4-(4-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7cf4-(4-(4-METHOXYBENZYLOXY)PHENYLAMINO)-6-NITRO-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7cg4-(4-(3-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-NITRO-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7ch6-NITRO-4-(PYRIDIN-2-YL-AMINO)-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7ci6-NITRO-7-(PYRIDIN-4-YL-OXY)-4-(PYRIMIDIN-2-YL-AMINO)QUINOLINE-3-CARBONITRILE

Preparation 7cj4-(6-(BENZYLOXY)PYRIDIN-3-YL-AMINO)-6-NITRO-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7ck4-(6-(3-CHLOROBENZYLOXY)PYRIDIN-3-YL-AMINO)-6-NITRO-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 7cl6-NITRO-4-(6-PHENOXYPYRIDIN-3-YL-AMINO)-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8a6-AMINO-4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

To a single-neck flask (500 mL) were added4-(3-chloro-4-(pyridin-2-yl-methoxy)benzenamide)-6-nitro-7-(tetrahydrofuran-3-yl-oxy)quinoline-3-carbonitrile (5.950 g, 11.498 mmol) and SnCl₂.2H₂O (12.935g). To the flask was added anhydrous ethanol (250 mL). The mixture wasstirred under reflux at the temperature of 85° C. After 1.5 hr, thereaction finished. The resultant mixture was rotary-evaporated todryness. To the resulting mixture was added water (150 mL). Theresultant mixture was ultrasonically treated and rotary-evaporated todryness. The resulting product was poured into water (300 mL). The pH ofthe mixture was adjusted to 8 with saturated NaHCO₃ solution. Thesolution was extracted with chloroform three times (700 mL in total) andthen extracted with ethyl acetate three times. The ethyl acetate layerswere combined and washed with saturated NaCl solution (300 mL). Theresultant organic phase was dried over anhydrous MgSO₄ for half-hour,filtered and rotary-evaporated to dryness. The resultant products werecombined and purified by column chromatography(chloroform:methanol=95:5) to give a yellow solid (2.881 g). Yield:51.4%.

The compounds of Preparation 8b to Preparation 8ck were preparedaccording to the process of Preparation 8a.

Preparation 8b6-AMINO-4-(3-CHLORO-4-FLUOROPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8c6-AMINO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8d6-AMINO-4-(3-BROMOPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8e6-AMINO-4-(1H-INDOL-5-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8f4-(4-(2-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8g4-(4-(3-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8h4-(4-(4-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8i4-(4-(2-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8j4-(4-(3-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8k4-(4-(4-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8l4-(4-(2-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8m4-(4-(3-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8n4-(4-(4-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8o4-(4-(2-METHOXYBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8p4-(4-(3-METHOXYBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8q4-(4-(4-METHOXYBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8r4-(4-(2-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8 s4-(4-(3-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8t4-(4-(4-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8u4-(4-(4-TERT-BUTYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8v6-AMINO-4-(4-(BENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8x4-(4-(2-CHLOROBENZYLOXY)-3-FLUOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8y4-(4-(3-CHLOROBENZYLOXY)-3-FLUOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8z4-(4-(4-CHLOROBENZYLOXY)-3-FLUOROPHENYLAMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8aa6-AMINO-4-((S)-1-PHENYLETHYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8ab6-AMINO-4-((R)-1-PHENYLETHYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8ac6-AMINO-4-(1-BENZYL-1H-INDOL-5-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8ad4-(1-(3-CYANOBENZYL)-1H-INDOL-5-YL-AMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8ae4-(1-(3-METHOXYBENZYL)-1H-INDOL-5-YL-AMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8af4-(1-(3-CHLOROBENZYL)-1H-INDOL-5-YL-AMINO)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8ag6-AMINO-4-(INDOLIN-1-YL)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8ah6-AMINO-4-(6-CHLOROINDOLIN-1-YL)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8ai6-AMINO-4-(6-FLUOROINDOLIN-1-YL)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8aj6-AMINO-4-(4-CHLOROINDOLIN-1-YL)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8ak 6-AMINO-4-(3,4-DIHYDROQUINOLIN-1(2H)-YL)-7-(TETRAHYDROFURAN-3-YL-OXY) QUINOLINE-3-CARBONITRILE

Preparation 8al 6-AMINO-4-(6-METHYL-3,4-DIHYDROQUINOLIN-1(2H)-YL)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8am6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)-4-(7-(TRIFLUOROMETHYL)-3,4-DIHYDROQUINOLIN-1(2H)-YL)QUINOLINE-3-CARBONITRILE

Preparation 8an6-AMINO-4-(6-(BENZYLOXY)INDOLIN-1-YL)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8ao METHYL 1-(6-AMINO-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL)INDOLINE-2-CARBOXYLATE

Preparation 8ap6-AMINO-4-(2-(HYDROXYMETHYL)INDOLIN-1-YL)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8aq4-(6-(1H-PYRROL-1-YL)INDOLIN-1-YL)-6-AMINO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8ar6-AMINO-4-(OCTAHYDROINDOL-1-YL)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8as6-AMINO-4-(PYRIMIDIN-2-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8atN-(2-(6-AMINO-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-5-YL)BENZAMIDE

Preparation 8auN-(2-(6-AMINO-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-5-YL)-4-(DIMETHYLAMINO)BENZAMIDE

Preparation 8avN-(2-(6-AMINO-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-5-YL)BENZENESULFONAMIDE

Preparation 8awN-(5-(6-AMINO-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-2-YL)BENZAMIDE

Preparation 8axN-(5-(6-AMINO-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-2-YL)FURAN-2-CARBOXAMIDE

Preparation 8ayN-(5-(6-AMINO-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-2-YL)THIOPHENE-2-CARBOXAMIDE

Preparation 8azN-(5-(6-AMINO-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-2-YL)CYCLOHEXYLCARBOXAMIDE

Preparation 8ba5-(6-AMINO-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN4-4-YL-AMINO)-N-(4-METHOXYPHENYL)PYRIMIDIN-2-YL-CARBOXAMIDE

Preparation 8bb6-AMINO-4-(PYRIDIN-2-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8bc6-(6-AMINO-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)-N-(4-METHOXYPHENYL)NICOTINAMIDE

Preparation 8bd6-AMINO-4-(PYRIDIN-3-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8be6-AMINO-4-(PYRIDIN-4-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8bf6-AMINO-4-(6-(BENZYLOXY)PYRIDIN-3-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8bg6-AMINO-4-(PYRAZIN-2-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8bh6-AMINO-4-(3-CHLORO-4-FLUOROPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)-QUINOLINE-3-CARBONITRILE

Preparation 8bi6-AMINO-4-(3-ETHYNYLPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8bj6-AMINO-4-(4-(BENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8bk4-(4-(2-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8bl4-(4-(3-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8bm4-(4-(4-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8bn4-(4-(4-BROMOBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8bo4-(4-(4-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8bp4-(4-(4-METHOXYBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8bq4-(4-(4-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8br4-(4-(4-ETHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8bs4-(4-(4-ETHOXYBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8bt6-AMINO-4-(3-CHLORO-4-PHENOXYPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8bu6-AMINO-7-(1-METHYLPIPERIDIN-4-YL-OXY)-4-(PYRIDIN-2-YL-AMINO)QUINOLINE-3-CARBONITRILE

Preparation 8bv6-AMINO-7-(1-METHYLPIPERIDIN-4-YL-OXY)-4-(PYRIDIN-3-YL-AMINO)QUINOLINE-3-CARBONITRILE

Preparation 8bw6-AMINO-7-(1-METHYLPIPERIDIN-4-YL-OXY)-4-(PYRIDIN-4-YL-AMINO)QUINOLINE-3-CARBONITRILE

Preparation 8bx6-AMINO-4-(6-(BENZYLOXY)PYRIDIN-3-YL-AMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8by6-AMINO-4-(3-CHLORO-4-FLUOROPHENYLAMINO)-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8bz 6-AMINO-4-(3-ETHYNYLPHENYLAMINO)-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8ca6-AMINO-4-(4-PHENOXYPHENYLAMINO)-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8cb6-AMINO-4-(4-(BENZYLOXY)PHENYLAMINO)-7-PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8cc4-(4-(2-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8cd4-(4-(4-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8ce4-(4-(4-METHOXYBENZYLOXY)PHENYLAMINO)-6-AMINO-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8cf4-(4-(3-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-6-AMINO-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8cg6-AMINO-4-(PYRIDIN-2-YL-AMINO)-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8ch6-AMINO-7-(PYRIDIN-4-YL-OXY)-4-(PYRIMIDIN-2-YL-AMINO)QUINOLINE-3-CARBONITRILE

Preparation 8ci6-AMINO-4-(6-(BENZYLOXY)PYRIDIN-3-YL-AMINO)-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8cj4-(6-(3-CHLOROBENZYLOXY)PYRIDIN-3-YL-AMINO)-6-AMINO-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 8ck6-AMINO-4-(6-PHENOXYPYRIDIN-3-YL-AMINO)-7-(PYRIDIN-4-YL-OXY)QUINOLINE-3-CARBONITRILE

Preparation 9 (E)-TRIMETHYLSILYL 4-BROMO-2-BUTENOATE

To a single-neck reaction flask (250 mL) were added of crotonic acid(10.750 g, 0.125 mol), anhydrous ethyl ether (125 mL) and trimethylchlorosilane (19 mL, 0.150 mol). The mixture was stirred for 5 min.Pyridine (12 mL, 0.150 mol) was dropwise added into the resultingmixture under stirring at the temperature of 35° C. After the additionfinished, the mixture was warmed up to the temperature of 38° C. andstirred under relux for 3 hr. The white solid was filtered in vacuo.Ethyl ether was evaporated under atmospheric pressure. The resultant wasdistilled under reduced pressure to collect the fraction under 10 mmHgat the temperature of 46° C.-48° C. to give (E)-trimethylsilyl2-butenoate as a colorless liquid (12.242 g). Yield: 62.0%.

To a single-neck reaction flask (250 mL) were added (E)-trimethylsilyl2-butenoate (12.242 g, 77.481 mmol), NBS (16.550 g, 92.977 mmol),(PhCO₂)₂ (310 mg) and carbon tetrachloride (100 mL). The mixture wasstirred under reflux for 3.5 hr. The resulting mixture was cooled in anice-water bath. The insoluble substance was filtered. The residue wasrotatory-evaporated and concentrated until no liquid dropped. Theconcentrate was distilled under reduced pressure to collect the fractionunder 9 mmHg at the temperature of 100° C.-102° C. to give the targetcompound as a colorless transparent liquid.

Preparation 10 (E/Z)-TRIMETHYLSILYL 4-BROMO-2-BUTENOATE

The compound was prepared according to the process of Preparation 9 with2-butenoic acid as starting material.

The compounds of Preparations 11, 12 and 13 were prepared according tothe preparation process disclosed in Chinese patent No. CN200610138377.9.

Preparation 11 2-(1-(TERT-BUTOXYCARBONYL)PIPERIDIN-4-YLIDENE)-ACETICACID

Preparation 12 2-(1-(2-METHOXYETHYL)-PIPERIDIN-4-YLIDENE)-ACETIC ACID

Preparation 13 (E)-2-(1-(TERT-BUTOXYCARBONYL)PYRROLIN-3-YLIDENE)ACETICACID Example 1(E)-4-BROMO-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-BUT-2-ENAMIDE

a) After a single-neck reaction flask (100 mL) was blown with argon for5 min, to the reaction flask was added (E)-trimethylsilyl4-bromo-2-butenoate (1.363 g, 5.75 mmol). DCM (treated with molecularsieves) (3 mL) was added under argon atmosphere. To the mixture wereadded oxalyl chloride (0.55 mL, 6.325 mmol) and one drop of DMF(chromatographically pure) under stirring. Lots of bubbles produced.After 1 min, the bubbles reduced. The resulting mixture was continuouslystirred for 2 hr at the room temperature and then rotary-evaporated todryness.

b)6-amino-4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-3-carbonitrile (2.44 g, 5 mmol) was dissolved inTHF (redistilled) (36 mL) under argon atmosphere. The solution wascooled in an ice-water bath. DIEA (1.73 mL, 10 mmol) was added. Theresulting solution was stirred for 10 min. The rotary-evaporated productfrom a) was dissolved in THF (redistilled) (14 mL). The resultantsolution was dropwise added into the reaction solution. The mixture wasstirred in an ice-water bath overnight. The resultant mixture wasrotary-evaporated to dryness. Ethyl acetate (200 mL) and saturatedNa₂CO₃ solution (150 mL) were added. The solution was stirred for 10 minat the room temperature. After separation, the aqueous layer wasextracted once with ethyl acetate (100 mL). The ethyl acetate layerswere combined. The organic phase was washed with water (200 mL) andsaturated NaCl solution (200 mL), dried over MgSO₄ for half-hour,filtered and rotary-evaporated to dryness. The resultant substance waspurified with column chromatography (eluent: chloroform:methanol=9:1) togive a yellow solid (2.381 g). Yield: 75.0%.

MS (M+1): 634.

H¹-NMR (CDCl₃): δ 2.222-2.270 (m, 1H); 2.346-2.476 (m, 1H); 3.431-3.458(m, 1H); 3.925-3.955 (m, 1H); 4.012-4.247 (m, 4H); 5.158 (br, 1H); 5.281(d, 2H, J=4.8); 6.114-6.422 (m, 2H); 6.905-7.198 (m, 3H); 7.535 (br,1H); 7.648 (d, 1H, J=6.6); 7.765 (t, 1H, J=6.8); 8.154 (d, 1H, J=76.9);8.485 (s, 1H); 8.596 (d, 2H, J=3.8); 9.109 (d, 1H, J=42.4).

Example 2(E)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

(E)-4-bromo-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-butenamide(2.35 g, 3.704 mmol) was dissolved in DMF (chromatographically pure) (40mL). The solution was cooled in an ice-water bath under argonatmosphere. To the solution was added NaI (278 mg, 1.852 mmol). Themixture was stirred for 30 min. To the mixture were added dimethylaminehydrochloride (604 mg, 7.408 mmol), potassium carbonate (2.556 g, 18.519mmol) and tetrabutyl ammonium iodide (59 mg, 0.185 mmol). The resultantmixture was stirred at the room temperature overnight. After thereaction finished, the reaction solution was poured into staturatedNaHCO₃ solution (400 mL) to precipitate a yellow solid. The solid wasextracted with ethyl acetate three times (550 mL in total). The ethylacetate layers were combined. The organic phase was washed with water(300 mL) and saturated NaCl solution (300 mL), successively. Theresultant organic phase was dried over anhydrous MgSO₄ for half-hour,filtered and rotary-evaporated to dryness. The resultant substance waspurified with column chromatography (eluent: chloroform:methanol=9:1) togive a yellow solid (1.375 g). Yield: 62.0%.

MS (M+1): 599.

H¹-NMR (DMSO-d₆, CH₃OH-d₄): δ 2.167-2.219 (m, 1H); 2.354-2.452 (m, 1H);2.782 (s, 6H); 3.794 (dd, 1H, J₁=8.0; J₂=14.0); 3.949-4.074 (m, 5H);5.258 (br, 1H); 5.546 (s, 2H); 6.795-6.914 (m, 2H); 7.387 (d, 1H,J=8.8); 7.551 (s, 1H); 7.674 (s, 1H); 7.845 (t, 1H, J=6.4); 8.000 (d,1H, J=7.8); 8.406 (t, 1H, J=7.6); 8.851 (d, 1H, J=5.2); 9.043 (s, 1H);9.231 (s, 1H).

Example 3(E)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEHYDROCHLORIDE

(E)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-2-butenamide wasdissolved in redistilled methanol (10 mL). A solution of HCl in ethylether (5 mL, 1.8 N) was dropwise added into the resultant solution understirring. The resulting mixture was stirred for 10 min androtary-evaporated to dryness. The resultant substance was recrystalizedwith a mixed solution of anhydrous methanol and hydrochloric acid (2 N)to give a crystal of(E)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-2-butenamide as hydrochloride(1.163 g).

MS (M+1): 599.

The compounds of Examples 4-21 were prepared according to the processfor preparing the compound of Example 2.

Example 4(E)-N-(4-(3-CHLORO-4-FLUOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 510

Example 5(E)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 482

The compound was prepared as hydrochloride according to the process ofExample 3 to determine H¹-NMR (DMSO-d₆): δ 2.173-2.218 (m, 1H);2.405-2.468 (m, 1H); 2.746 (s, 3H); 2.755 (s, 3H); 3.774-3.831 (m, 1H);3.956-4.103 (m, 5H); 4.315 (s, 1H); 5.270 (br, 1H); 6.826-6.968 (m, 2H);7.500 (s, 3H); 7.559 (s, 1H); 7.768 (s, 1H); 9.074 (s, 1H); 9.219 (s,1H); 10.037 (s, 1H); 11.340 (br, 2H).

Example 6(E)-N-(4-(4-(BENZYLOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 564

Example 7(E)-N-(4-(3-BROMOPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 536

The compound was prepared as hydrochloride according to the process ofExample 3 to determine H¹-NMR (DMSO-d₆): δ 2.157-2.216 (m, 1H);2.385-2.456 (m, 1H); 2.741 (s, 3H); 2.753 (s, 3H); 3.803 (dd, 1H,J₁=8.0, J₂=13.6); 3.939-4.103 (m, 5H); 5.266 (br, 1H); 6.826-6.968 (m,2H); 7.431-7.466 (m, 2H); 7.587-7.608 (m, 1H); 7.718 (s, 1H); 7.786 (s,1H); 9.110 (s, 1H); 9.222 (s, 1H); 10.052 (s, 1H); 11.345 (br, 2H).

Example 8(E)-N-(4-(4-(2-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 616

The compound was prepared as hydrochloride according to the process ofExample 3 to determine H¹-NMR (DMSO-d₆): δ 2.148-2.211 (m, 1H);2.380-2.452 (m, 1H); 2.744 (s, 3H); 2.755 (s, 3H); 3.803 (dd, 1H,J₁=8.0, J₂=13.6); 3.943-4.098 (m, 5H); 5.256 (br, 1H); 5.310 (s, 2H);6.816-6.971 (m, 2H); 7.258-7.321 (m, 2H); 7.417-7.473 (m, 3H);7.607-7.652 (m, 2H); 7.750 (s, 1H); 9.082 (s, 1H); 9.203 (s, 1H); 10.056(s, 1H); 11.312 (br, 2H).

Example 9(E)-N-(4-(4-(3-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 616

The compound was prepared as hydrochloride according to the process ofExample 3 to determine H¹-NMR (CDCl₃, CH₃OH-d₄): δ 2.168-2.202 (m, 1H);2.425-2.482 (m, 1H); 2.747 (s, 3H); 2.750 (s, 3H); 3.798-3.835 (m, 1H);3.960-4.121 (m, 5H); 5.250 (br, 1H); 5.325 (s, 2H); 6.834-6.967 (m, 2H);7.174-7.219 (m, 1H); 7.311-7.361 (m, 2H); 7.461 (q, 2H, J=7.2); 7.674(s, 1H); 7.822 (s, 1H); 9.090 (s, 1H); 9.212 (s, 1H); 10.085 (s, 1H);11.387 (s, 1H); 11.441 (s, 1H).

Example 10(E)-N-(4-(4-(2-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 632

The compound was prepared as hydrochloride according to the process ofExample 3 to determine H¹-NMR (DMSO-d₆): δ 2.148-2.213 (m, 1H);2.399-2.452 (m, 1H); 2.746 (s, 3H); 2.757 (s, 3H); 3.804 (dd, 1H,J₁=8.0, J₂=13.6); 3.955-4.097 (m, 5H); 5.262 (br, 1H); 5.327 (s, 2H);6.816-6.968 (m, 2H); 7.394-7.465 (m, 3H); 7.545-7.568 (m, 1H);7.664-7.686 (m, 2H); 7.741 (s, 1H); 9.078 (s, 1H); 9.205 (s, 1H); 10.054(s, 1H); 11.316 (br, 2H).

Example 11(E)-N-(4-(4-(3-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 632

The compound was prepared as hydrochloride according to the process ofExample 3 to determine H¹-NMR (DMSO-d₆): δ 2.150-2.211 (m, 1H);2.385-2.454 (m, 1H); 2.743 (s, 3H); 2.751 (s, 3H); 3.801 (dd, 1H,J₁=8.0, J₂=13.2); 3.954-4.097 (m, 5H); 5.249 (br, 1H); 5.314 (s, 2H);6.824-6.977 (m, 2H); 7.347 (d, 1H, J=8.8); 7.426-7.473 (m, 4H); 7.568(s, 1H); 7.668 (d, 1H, J=2.4); 7.790 (s, 1H); 9.080 (s, 1H); 9.203 (s,1H); 10.066 (s, 1H); 11.334 (s, 1H); 11.413 (br, 1H).

Example 12(E)-N-(4-(4-(BENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 598

The compound was prepared as hydrochloride according to the process ofExample 3 to determine H¹-NMR (DMSO-d₆): δ 2.152-2.214 (m, 1H);2.382-5.452 (m, 1H); 2.741 (s, 3H); 2.752 (s, 3H); 3.801 (dd, 1H,J₁=7.6, J₂=13.6); 3.936-4.091 (m, 5H); 5.254 (br, 1H); 5.282 (s, 2H);6.818-6.975 (m, 2H); 7.345-7.379 (m, 2H); 7.408-7.446 (m, 3H);7.495-7.513 (m, 2H); 7.642 (d, 1H, J=2.4); 7.778 (s, 1H); 9.055 (s, 1H);9.195 (s, 1H); 10.028 (s, 1H); 11.292 (s, 1H); 11.418 (br, 1H).

Example 13(E)-N-(4-(4-(2-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 623

The compound was prepared as hydrochloride according to the process ofExample 3 to determine H¹-NMR (DMSO-d₆): δ 2.150-2.211 (m, 1H);2.374-2.443 (m, 1H); 2.749 (s, 3H); 2.759 (s, 3H); 3.805 (dd, 1H,J₁=7.6, J₂=13.2); 3.938-4.089 (m, 5H); 5.271 (br, 1H); 5.420 (s, 2H);6.802-6.955 (m, 2H); 7.433 (s, 2H); 7.601-7.678 (m, 3H); 7.790 (s, 1H);7.800 (s, 1H); 7.953 (d, 1H, J=8.0); 9.024 (s, 1H); 9.178 (s, 1H); 9.987(s, 1H); 11.166 (br, 2H).

Example 14(E)-N-(4-(4-(4-TERT-BUTYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 654

The compound was prepared as hydrochloride according to the process ofExample 3 to determine H¹-NMR (DMSO-d₆): δ 1.268 (s, 9H); 2.121-2.181(m, 1H), 2.353-2.422 (m, 1H); 2.713 (s, 3H); 2.724 (s, 3H); 3.771 (dd,1H, J₁=8.0, J₂=13.6); 3.913-4.067 (m, 5H); 5.198 (s, 2H); 5.271 (br,1H); 6.787-6.938 (m, 2H); 7.327-7.432 (s, 6H); 7.619 (d, 1H, J=2.8);7.725 (s, 1H); 9.057 (s, 1H); 9.175 (s, 1H); 10.036 (s, 1H); 11.309 (br,2H).

Example 15(E)-N-(4-(4-(3-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 623

The compound was prepared as hydrochloride according to the process ofExample 3 to determine H¹-NMR (DMSO-d₆): δ 2.150-2.197 (m, 1H);2.380-2.451 (m, 1H); 2.748 (s, 3H); 2.758 (s, 3H); 3.803 (dd, 1H,J₁=8.0, J₂=13.6); 3.957-4.098 (m, 5H); 5.259 (br, 1H); 5.365 (s, 2H);6.821-6.968 (m, 2H); 7.360 (d, 1H, J=8.8); 7.440 (d, 1H, J=8.8);7.641-7.673 (m, 2H); 7.744 (br, 1H); 7.840 (s, 1H); 7.859 (s, 1H); 7.939(s, 1H); 9.070 (s, 1H); 9.201 (s, 1H); 10.062 (s, 1H); 11.317 (br, 2H).

Example 16(E)-N-(4-(4-(4-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 632

The compound was prepared as hydrochloride according to the process ofExample 3 to determine H¹-NMR (DMSO-d₆): δ 2.147-2.209 (m, 1H);2.381-2.452 (m, 1H); 2.742 (s, 3H); 2.753 (s, 3H); 3.801 (dd, 1H,J₁=8.0, J₂=13.6); 3.942-4.096 (m, 5H); 5.253 (br, 1H); 5.290 (s, 2H);6.818-6.972 (m, 2H); 7.345 (d, 1H, J=8.8); 7.429 (dd, 1H, J₁=2.4,J₂=8.8); 7.512 (dd, 1H, J₁=8.4, J₂=14.8); 7.655 (d, 1H, J=2.4); 7.763(s, 1H); 9.074 (s, 1H); 9.198 (s, 1H); 10.059 (s, 1H); 11.305 (s, 1H);11.360 (br, 1H).

Example 17(E)-N-(4-(4-(2-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 612

The compound was prepared as hydrochloride according to the process ofExample 3 to determine H¹-NMR (DMSO-d₆): δ 2.164-2.195 (m, 1H); 2.368(s, 3H); 2.403-2.454 (m, 1H); 2.744 (s, 6H); 3.774-3.809 (m, 1H);3.955-4.097 (m, 5H); 5.260 (s, 3H); 6.824-6.975 (m, 2H); 7.236-7.283 (m,3H); 7.413-7.498 (m, 3H); 7.651 (s, 1H); 7.780 (s, 1H); 9.082 (s, 1H);9.208 (s, 1H); 10.069 (s, 1H); 11.348 (br, 2H).

Example 18(E)-N-(4-(4-(3-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 612

Example 19(E)-N-(4-(4-(4-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 612

The compound was prepared as hydrochloride according to the process ofExample 3 to determine H¹-NMR (DMSO-d₆): δ 2.148-2.194 (m, 1H); 2.325(s, 3H); 2.396-2.448 (m, 1H); 2.743 (s, 3H); 2.754 (s, 3H); 3.801 (dd,1H, J₁=8.0, J₂=13.6); 3.953-4.094 (m, 5H); 5.221 (s, 2H); 5.256 (br,1H); 6.815-6.968 (m, 2H); 7.220 (s, 1H); 7.239 (s, 1H); 7.331-7.423 (m,4H); 7.632 (d, 1H, J=2.4); 7.739 (s, 1H); 9.059 (s, 1H); 9.190 (s, 1H);10.049 (s, 1H); 11.259 (br, 1H); 11.335 (br, 1H).

Example 20(E)-N-(3-CYANO-4-((R)-1-PHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE MS (M+1): 486

Example 21(E)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 599

Example 22N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)ACRYLAMIDE

To a reaction flask were added6-amino-4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-3-carbonitrile (100mg, 0.205 mmol), pyridine (0.3 ml), DMAP (20 mg) and THF (10 ml). Themixture was cooled to the temperature of 0° C. To the mixture was addedacryloyl chloride (20 mg, 0.22 mmol). The resultant mixture was stirredfor 30 min at the temperature of 0° C. Then the mixture was warmed tothe room temperature and stirred for 5 hr. After the reaction finished,the resultant mixture was filtered and the filtrate wasrotary-evaporated to dryness to give a solid. The solid was dissolved inethyl acetate. The solution was washed with saturated sodium carbonateonce, acetic acid solution (10%) once and saturated saline once,successively. The resulting solution was dried over anhydrous magnesiumsulfate, filtered and rotary-evaporated to dryness to give a crudeproduct. The product was purified with thin layer chromatography.

MS (M+1): 542.

The compounds of Examples 23-28 were prepared according to the processof Example 22.

Example 23(E)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)BUT-2-ENAMIDEMS (M+1): 556

Example 24N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-3-METHYLBUT-2-ENAMIDEMS (M+1): 570

Example 25N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)PROPIOLAMIDEMS (M+1): 540

Example 26N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)PROPIOLAMIDEMS (M+1): 544

Example 27N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)ACETAMIDE

MS (M+1): 530

H¹-NMR (DMSO-d₆): δ 2.181 (br, 4H), 62.326-2.393 (m, 1H); 3.805 (dd, 1H,J₁=7.2, J₂=12.8); 3.955 (dd, 1H, J₁=7.6, J₂=14.4); 4.017-4.058 (m, 2H);5.279 (br, 1H); 5.319 (s, 2H); 7.303 (s, 1H); 7.375-7.444 (m, 2H); 7.521(s, 1H); 7.593 (d, 1H, J=8.4); 7.893 (t, 1H, J=8.0); 8.617 (s, 1H);8.752 (s, 1H); 8.967 (s, 1H); 9.442 (s, 1H).

Example 28N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)BENZAMIDE

MS (M+1): 592

H¹-NMR (DMSO-d₆): δ 2.087-2.132 (m, 1H); 2.287-2.376 (m, 1H);3.769-3.820 (m, 1H); 3.859-3.948 (m, 2H); 4.019 (dd, 1H, J₁=4.4;J₂=10.0); 5.298 (s, 2H); 5.348 (br, 1H); 7.234-7.267 (m, 2H);7.360-7.390 (m, 1H); 7.438 (s, 1H) 7.449 (s, 1H); 7.556-7.650 (m, 4H);7.877 (t, 1H, J=8.0); 7.889 (d, 2H, J=7.2); 8.324 (s, 1H); 8.527 (s,1H); 8.603 (d, 1H, J=4.4); 8.821 (s, 1H); 9.757 (s, 1H); 9.808 (s, 1H).

Example 29 TERT-BUTYL4-(2-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL-AMINO)-2-OXOETHYLIDENE)PIPERIDINE-1-CARBOXYLATE

To a single-neck reaction flask (100 ml) were added2-(1-(tert-butyloxycarbonyl)piperidin-4-ylidene)acetic acid (1 g) andanhydrous THF (20 ml). The mixture was stirred to dissolve and cooled tothe temperature of −5° C. To the mixture were added isobutylchloroformate (0.6 ml) and N-methylmorphine (0.5 ml). The resultantmixture was stirred for 20 min.6-amino-4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-3-carbonitrile (2 g,4.1 mmol) was dissolved in anhydrous pyridine (20 ml). The resultingsolution was added into the reaction flask in an ice-water bath. Afterthe reaction finished, the solvent was rotary-evaporated to dryness. Tothe residue were added chloroform and water. The solution was stood forseparation. The chloroform layer was wash once with saturated salinesolution, dried over anhydrous magnesium sulfate, filtered androtary-evaporated to dryness to give a crude product. The product wasrecrystalized with ethanol.

MS (M+1): 711.

Example 30N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE

The product of Example 29 (100 mg) was dissolved in 20% TFA/DCM solution(20 ml). The solution was stirred for 2 hr at the room temperature. Thenthe solvent was rotary-evaporated to dryness. The residue was dissolvedin chloroform. The organic phase was washed with staturated sodiumcarbonate once and saline solution once, successively. The resultantsubstance was dried over anhydrous magnesium sulfate and filtered. Thenthe solvent was rotary-evaporated to dryness to give the targetcompound.

MS (M+1): 611.

The compound was prepared as hydrochloride according to the process ofExample 3 to determine, H¹-NMR (DMSO-d₆): δ 2.168-2.209 (m, 1H);62.408-2.451 (m, 1H); 2.576 (bs, 2H); 3.133 (bs, 2H); 3.211 (s, 2H);3.259 (s, 2H); 3.805-3.830 (m, 1H); 3.939-4.114 (m, 5H); 5.258 (br, 1H);5.497 (s, 2H); 6.374 (s, 1H); 7.401 (d, 2H, J=8.4); 7.401 (d, 1H,J=8.4); 7.464 (d, 1H, J=8.4); 7.678 (br, 1H); 7.705 (s, 1H); 7.783-7.852(m, 2H); 8.173-8.214 (m, 1H); 8.785 (s, 1H); 9.090 (s, 1H); 9.213 (s,1H); 9.468 (br, 1H); 9.710 (s, 1H); 11.342 (br, 2H).

Example 31N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(1-METHYLPIPERIDIN-4-YLIDENE)ACETAMIDE

To a single-neck reaction flask (50 ml) was added the product of Example30 (20 mg). The product was dissolved in acetonitrile (10 ml). To theresultant solution were added anhydrous potassium carbonate powders (20mg) and methyl iodide (5 mg). The resulting mixture was stirred at theroom temperature. After the reaction finished, the resultant substancewas filtered. The filtrate was rotary-evaporated to dryness to give acrude product. The crude product was purified with thin layerchromatography (developing solvent: chloroform:methanol=92:8).

MS (M+1): 625.

The compounds of Examples 32-37 were prepared according to the processof Example 31.

Example 32N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(1-ETHYLPIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 639

Example 332-(1-BENZYLPIPERIDIN-4-YLIDENE)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)ACETAMIDEMS (M+1): 701

Example 34N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(1-(2-METHOXYETHYL)PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 669

Example 35 Methyl2-(4-(2-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL-AMINO)-2-OXOETHYLIDENE)PIPERIDIN-1-YL)ACETATEMS (M+1): 683

Example 36N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(1-ISOPROPYLPIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 653

Example 37N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(1-(2-HYDROXYETHYL)PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 655

Example 38(E/Z)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PYRROLIDIN-3-YLIDENE)ACETAMIDEMS (M+1): 597

In accordance with the process of Examples 29 and 30, the targetcompound was prepared by replacing2-(1-(tert-butoxycarbonyl)piperidin-4-ylidene)acetic acid with(E/Z)-2-(1-(tert-butoxycarbonyl)pyrrolin-3-ylidene)acetic acid.

Example 39N¹-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-N⁴-(2-(2-(DIMETHYLAMINO)ETHOXY)ETHYL)FUMARAMIDE

To a single-neck reaction flask (50 ml) were added6-amino-4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinoline-3-carbonitrile(20 mg, 0.041 mmol), maleic acid (4 mg), pyridine (0.1 ml) and THF (5ml), The mixture was stirred at the room temperature. After the reactionfinished, the solvent was rotary-evaporated to dryness. The residue waspurified with thin layer chromatography (developing solvent:chloroform:methanol:acetic acid=450:50:2). The resulting pure productwas dissolved in anhydrous THF. Aminoethoxyethanol was added into theresultant solution. The mixture was cooled in an ice bath. DCC (8 mg)was dissolved in anhydrous THF (5 ml). The resulting solution wasdropwise added into the reaction flask under continuously stirring.After the reaction finished, the solvent was rotary-evaporated todryness to give a crude product. The crude product was dissolved inpyridine (5 ml). p-toluene sulfonyl chloride (7 mg) was added into theresultant solution. The mixture was stirred at the room temperature.After the reaction finished, the solvent was rotary-evaporated todryness. The resulting crude product was dissolved in chloroform. Theorganic phase was washed with staturated sodium carbonate once, HCl (1N) once and saturated saline solution once, successively. The resultantsubstance was dried over anhydrous magnesium sulfate, filtered androtary-evaporated to dryness to give a product. The above resultingproduct was dissolved in pyridine (10 ml). Dimethylamine was added intothe solution. The resultant mixture was stirred at the room temperature.After the reaction finished, the solvent was rotary-evaporated todryness. The resultant substance was purified with thin layerchromatography, (developing solvent:chloroform:methanol=9:1) to give thetargent compound.

MS (M+1): 700.

Example 40N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(1-(2-(2-(2-HYDROXYETHOXY)ETHYLAMINO)ACETYL)PIPERIDIN-4-YLIDENE)ACETAMIDE

To a single-neck reaction flask (50 ml) were addedN-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide(20 mg, 0.041 mmol) and anhydrous THF (10 ml). The solution was cooledin an ice bath. Chloroacetyl chloride (4.5 mg) and anhydroustriethylamine (0.02 ml) were added into the solution. The resultantmixture was continuously stirred. After the reaction finished, thesolvent was rotary-evaporated to dryness. The residue was dissolved inchloroform. The solution was washed with water three times and withsaturated saline solution once. The resultant solution was dried overanhydrous magnesium sulfate, filtered and rotary-evaporated to dryness.The above resulting crude product was dissolved in acetonitrile (10 ml).To the solution were added aminoethoxyethanol (4 mg) and triethylamine(0.2 ml). The mixture was stirred at the room temperature. After thereaction finished, the solvent was rotary-evaporated to dryness. Theresultant substance was purified with thin layer chromatography(developing solvent:chloroform methanol=9:1.

MS (M+1): 756.

Example 41N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(1-(METHYLSULFONYL)PIPERIDIN-4-YLIDENE)ACETAMIDE

In accordance with the process of Example 22, the compound was preparedby replacing acryloyl chloride with methylsulfonyl chloride.

MS (M+1): 689.

The compounds of Examples 42-132 were prepared according to theprocesses of Examples 29 and 30.

Example 42N-(4-(3-CHLORO-4-FLUOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE

MS (M+1): 522

The compound was prepared as hydrochloride according to the process ofExample 3 to determine H¹-NMR (DMSO-d₆): δ 2.143-2.214 (m, 1H);62.372-2.443 (m, 1H); 2.561 (bs, 2H); 3.123 (bs, 2H); 3.169-3.240 (m,4H); 3.803 (dd, 1H, J₁=8.0, J₂=13.6); 3.927-4.099 (m, 5H); 5.258 (br,1H); 6.357 (s, 1H); 7.507 (br, 1H); 7.567 (t, 1H, J=9.0); 7.744-7.794(m, 2H); 9.069 (s, 1H); 9.170 (s, 1H); 9.409 (br, 2H); 9.651 (s, 1H);11.248 (s, 1H).

Example 43N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 494

Example 44N-(4-(3-BROMOPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 548

Example 45N-(4-(4-(2-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 628

Example 46N-(4-(4-(3-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 628

Example 47N-(4-(4-(4-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 628

Example 48N-(4-(4-(2-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 644

Example 49N-(4-(4-(3-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS/(M+1) 644

Example 50N-(4-(4-(4-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 644

Example 51N-(4-(4-(2-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 624

Example 52N-(4-(4-(3-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 624

Example 53N-(4-(4-(4-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 624

Example 54N-(4-(4-(2-METHOXYBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 640

Example 55N-(4-(4-(3-METHOXYBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 640

Example 56N-(4-(4-(4-METHOXYBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 640

Example 57N-(4-(4-(2-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 635

Example 58N-(4-(4-(3-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 635

Example 59N-(4-(4-(4-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 635

Example 60N-(4-(4-(4-TERT-BUTYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 666

Example 61N-(4-(4-(BENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 610

Example 62N-(4-(1H-INDOL-5-YL-AMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 509

Example 63N-(4-(4-(2-CHLOROBENZYLOXY)-3-FLUOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 628

Example 64N-(4-(4-(3-CHLOROBENZYLOXY)-3-FLUOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 628

Example 65N-(4-(4-(4-CHLOROBENZYLOXY)-3-FLUOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 628

Example 66N-(3-CYANO-4-((S)-1-PHENYLETHYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 498

Example 67N-(3-CYANO-4-((R)-1-PHENYLETHYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 498

Example 68N-(4-(1-BENZYL-1H-INDOL-5-YL-AMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 599

Example 69N-(4-(1-(3-CYANOBENZYL)-1H-INDOL-5-YL-AMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 624

Example 70N-(4-(1-(3-METHOXYBENZYL)-1H-INDOL-5-YL-AMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 629

Example 71N-(4-(1-(3-CHLOROBENZYL)-1H-INDOL-5-YL-AMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 633

Example 72N-(3-CYANO-4-(INDOLIN-1-YL)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 496

Example 73N-(4-(6-CHLOROINDOLIN-1-YL)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 530

Example 74N-(3-CYANO-4-(6-FLUOROINDOLIN-1-YL)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1) 514

Example 75N-(4-(4-CHLOROINDOLIN-1-YL)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1) 530

Example 76N-(3-CYANO-4-(3,4-DIHYDROQUINOLIN-1(2H)-YL)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 510

Example 77N-(3-CYANO-4-(6-METHYL-3,4-DIHYDROQUINOLIN-1(2H)-YL)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 524

Example 78N-(3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)-4-(7-(TRIFLUOROMETHYL)-3,4-DIHYDROQUINOLIN-1(2H)-YL)-QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE) ACETAMIDE MS (M+1): 578

Example 79N-(4-(6-(BENZYLOXY)INDOLIN-1-YL)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 602

Example 80 METHYL1-(3-CYANO-6-(2-(PIPERIDIN-4-YLIDENE)ACETAMIDO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL)-INDOLINE-2-CARBOXYLATEMS (M+1): 554

Example 81N-(3-CYANO-4-(2-(HYDROXYMETHYL)INDOLIN-1-YL)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 526

Example 82N-(4-(6-(1HH-PYRROL-1-YL)INDOLIN-1-YL)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 561

Example 83N-(3-CYANO-4-(OCTAHYDROINDOL-1-YL)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 502

Example 84N-(3-CYANO-4-(PYRIMIDIN-2-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 472

Example 85N-(2-(3-CYANO-6-(2-(PIPERIDIN-4-YLIDENE)ACETAMIDO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-5-YL)BENZAMIDE MS (M+1): 591

Example 86N-(2-(3-CYANO-6-(2-(PIPERIDIN-4-YLIDENE)ACETAMIDO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-5-YL)-4-(DIMETHYLAMINO)BENZAMIDEMS (M+1): 634

Example 87N-(3-CYANO-4-(5-(PHENYLSULFONAMIDO)PYRIMIDIN-2-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 627

Example 88N-(5-(3-CYANO-6-(2-(PIPERIDIN-4-YLIDENE)ACETAMIDO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-2-YL)BENZAMIDE MS (M+1): 591

Example 89N-(5-(3-CYANO-6-(2-(PIPERIDIN-4-YLIDENE)ACETAMIDO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-2-YL)FURAN-2-CARBOXAMIDE MS (M+1): 581

Example 90N-(5-(3-CYANO-6-(2-(PIPERIDIN-4-YLIDENE)ACETAMIDO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-2-YL)THIOPHENE-2-CARBOXAMIDE MS (M+1): 597

Example 91N-(5-(3-CYANO-6-(2-(PIPERIDIN-4-YLIDENE)ACETAMIDO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)PYRIMIDIN-2-YL)CYCLOHEXYLCARBOXAMIDE MS (M+1): 597

Example 925-(3-CYANO-6-(2-(PIPERIDIN-4-YLIDENE)ACETAMIDO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)-N-(4-METHOXYPHENYL)PYRIMIDIN-2-CARBOXAMIDEMS (M+1): 621

Example 93N-(3-CYANO-4-(PYRIDIN-2-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1)-471

Example 946-(3-CYANO-6-(2-(PIPERIDIN-4-YLIDENE)ACETAMIDO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-4-YL-AMINO)-N-(4-METHOXYPTHENYL)NICOTINAMIDEMS (M+1): 620

Example 95N-(3-CYANO-4-(PYRIDIN-3-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 471

Example 96N-(3-CYANO-4-(PYRIDIN-4-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 471

Example 97N-(4-(6-(BENZYLOXY)PYRIDIN-3-YL-AMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 577

Example 98N-(3-CYANO-4-(PYRAZIN-2-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1) 472

Example 99N-(4-(3-CHLORO-4-FLUOROPHENYLAMINO)-3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 549

Example 100N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 521

Example 101N-(4-(4-(BENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 637

Example 102N-(4-(4-(2-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 671

Example 103N-(4-(4-(3-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 671

Example 104N-(4-(4-(4-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 671

Example 105N-(4-(4-(4-BROMOBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 715

Example 106N-(4-(4-(4-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 651

Example 107N-(4-(4-(4-METHOXYBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 667

Example 108N-(4-(4-(4-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 662

Example 109N-(4-(4-(4-ETHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 665

Example 110N-(4-(4-(4-ETHOXYBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 681

Example 111N-(4-(3-CHLORO-4-PHENOXYPHENYLAMINO)-3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 623

Example 112N-(3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)-4-(PYRIDIN-2-YL-AMINO)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 498

Example 113N-(3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)-4-(PYRIDIN-3-YL-AMINO)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 498

Example 114N-(3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)-4-(PYRIDIN-4-YL-AMINO)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 498

Example 115N-(4-(6-(BENZYLOXY)PYRIDIN-3-YL-AMINO)-3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 604

Example 116N-(4-(3-CHLORO-4-FLUOROPHENYLAMINO)-3-CYANO-7-(PYRIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 529

Example 117N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(PYRIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 501

Example 118N-(3-CYANO-4-(4-PHENOXYPHENYLAMINO)-7-(PYRIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 569

Example 119 N-(4-(4-(BENZYLOXY)PHENYLAMINO)-3-CYANO-7-(PYRIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 583

Example 120N-(4-(4-(2-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(PYRIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 651

Example 121N-(4-(4-(4-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(PYRIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 631

Example 122N-(4-(4-(4-METHOXYBENZYLOXY)PHENYLAMINO)-3-CYANO-7-(PYRIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 613

Example 123N-(4-(4-(3-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(PYRIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 642

Example 124 N-(3-CYANO-4-(PYRIDINE-2-YL-AMINO)-7-(PYRIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 478

Example 125 N-(3-CYANO-7-(PYRIDIN-4-YL-OXY)-4-(PYRIMIDIN-2-YL-AMINO)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1) 479

Example 126N-(4-(6-(BENZYLOXY)PYRIDIN-3-YL-AMINO)-3-CYANO-7-(PYRIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE MS (M+1): 584

Example 127N-(4-(6-(3-CHLOROBENZYLOXY)PYRIDIN-3-YL-AMINO)-3-CYANO-7-(PYRIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 618

Example 128N-(3-CYANO-4-(6-(PHENOXYPYRIDIN-3-YL-AMINO)-7-(PYRIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDE

Example 129N-(4-(3-CHLORO-4-(PYRIDINE-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(PYRIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PIPERIDIN-4-YLIDENE)ACETAMIDEMS (M+1): 611

Example 130(E/Z)-N-(3-CYANO-4-(6-(PHENOXYPYRIDIN-3-YL-AMINO)-7-(PYRIDIN-4-YL-OXY)QUINOLIN-6-YL)-2-(PYRROLIDIN-3-YLIDENE)ACETAMIDEMS (M+1): 556

Example 131(E/Z)-N-(3-CYANO-7-(1-METHYLPIPERIDIN-4-YL-OXY)-4-(6-(PHENOXYPYRIDIN-3-YL-AMINO)QUINOLIN-6-YL)-2-(PYRROLIDIN-3-YLIDENE)ACETAMIDEMS (M+1): 576

Example 132(E/Z)-N-(3-CYANO-4-(6-(PHENOXYPYRIDIN-3-YL-AMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-2-(PYRROLIDIN-3-YLIDENE)ACETAMIDE MS (M+1):549

Example 1334-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-6-METHOXY-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

The target compound was prepared according to the process disclosed inChinese patent No. ZL 03815201.0.

MS (M+1): 503.

Example 1344-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-6-(PIPERIDIN-1-YL)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE

To a single-neck reaction flask (50 ml) were added6-amino-4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-3-carbonitrile (20 mg, 0.041 mmol), anhydrous potassium carbonate powder (10 mg) andchloroform (5 ml). To the flask was added 1,5-dibromopentane (10 mg).The mixture was stirred at the room temperature. After the reactionfinished, the mixture was filtered. The filtrate was rotary-evaporatedto dryness. The residue was purified with thin layer chromatography(developing solvent:chloroform:methanol=9:1) to give a pure product.

MS (M+1): 556.

The compounds of Examples 135-137 were prepared according to the processdisclosed in Chinese patent No. ZL 03815201.0.

Example 1354-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-6-(2-METHOXYETHOXY)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILEMS (M+1): 547

Example 1364-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-6-(2-(2-METHOXYETHOXY)ETHOXY)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILE MS (M+1): 591

Example 1374-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-6-(2-MORPHOLINOETHOXY)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLINE-3-CARBONITRILEMS (M+1): 602

The compounds of Examples 138-206 were prepared according to the processof Example 2.

Example 138(S,E)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 599

The compound was prepared as hydrochloride according to the process ofExample 3 so as to determine the specific rotation (the measurementconditions: 20° C., sodium lamp, D light, 589 nm): +51.4°

Example 139(R,E)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 599

Example 140(S,E)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 482

The compound was prepared as hydrochloride according to the process ofExample 3 to determine H¹-NMR (DMSO-d₆): δ 2.144-2.232 (m, 1H);2.375-2.469 (m, 1H); 2.741 (s, 3H); 2.756 (s, 3H); 3.765-3.837 (dd, 1H,J₁=10.8; J₂=16.0); 3.930-4.109 (m, 5H); 4.327 (s, 1H); 5.246 (br, 1H);6.839-6.997 (m, 2H); 7.508-7.511 (m, 3H); 7.576 (s, 1H); 7.848 (s, 1H);9.080 (s, 1H); 9.226 (s, 1H); 10.081 (s, 1H); 11.356 (br, 1H); 11.505(br, 1H).

Specific rotation (the measurement conditions: 20° C., sodium lamp, Dlight, 589 nm): +10.3°

Example 141(R,E)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 482

Example 142(S,E)-N-(4-(3-CHLORO-4-FLUOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 510

The compound was prepared as hydrochloride according to the process ofExample 3 so as to determine the specific rotation (the measurementconditions: 20° C., sodium lamp, D light, 589 nm): +21.2°

Example 143(S,E)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 510

Example 144(S,E)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(PIPERIDIN-1-YL)-BUT-2-ENAMIDEMS (M+1): 522

Example 145(S,E)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(MORPHOLIN-4-YL)-BUT-2-ENAMIDEMS (M+1): 524

Example 146(S,E)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(TERT-BUTYLAIMINO)-BUT-2-ENAMIDEMS (M+1): 510

Example 147(S,E)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(BENZYLAMINO)-BUT-2-ENAMIDEMS (M+1): 544

Example 148(S,E)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(6-HYDROXYHEXYLAIMINO)-BUT-2-ENAMIDEMS (M+1): 552

Example 149(S,E)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(N-METHYLBENZYLAMINO)-BUT-2-ENAMIDEMS (M+1): 558

Example 150(S,E)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 627

Example 151(S,E)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(PIPERIDIN-1-YL)-BUT-2-ENAMIDEMS (M+1): 639

Example 152(S,E)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(MORPHOLIN-4-YL)-BUT-2-ENAMIDEMS (M+1): 641

Example 153(S,E)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(TERT-BUTYLAMINO)-BUT-2-ENAMIDEMS (M+1): 627

Example 154(S,E)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFUTAN-3-YL-OXY)QUINOLIN-6-YL)-4-(6-HYDROXYHEXYLAMINO)-BUT-2-ENAMIDE MS (M+1): 671

Example 155(S,E)-N-(4-(4-(BENZYLOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 564

Example 156(S,E)-N-(4-(3-BROMOPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1) 536

Example 157(S,E)-N-(4-(4-(2-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 616

Example 158(S,E)-N-(4-(4-(3-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 616

Example 159(S,E)-N-(4-(4-(2-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 632

Example 160(S,E)-N-(4-(4-(3-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 632

Example 161(S,E)-N-(4-(4-(BENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 598

Example 162(S,E)-N-(4-(4-(2-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 623

Example 163(S,E)-N-(4-(4-(4-TERT-BUTYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 654

Example 164(S,E)-N-(4-(4-(3-CYANOBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 623

Example 165(S,E)-N-(4-(4-(4-CHLOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 632

Example 166(S,E)-N-(4-(4-(2-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 612

Example 167(S,E)-N-(4-(4-(4-METHYLBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 612

Example 168(S,E)-N-(4-(3-CHLORO-4-FLUOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIETHYLAMINO)-BUT-2-ENAMIDEMS (M+1) 538

Example 169(S,E)-N-(4-(3-CHLORO-4-FLUOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(PIPERIDIN-1-YL)-BUT-2-ENAMIDEMS (M+1): 550

Example 170(S,E)-N-(4-(3-CHLORO-4-FLUOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(MORPHOLIN-4-YL)-BUT-2-ENAMIDEMS (M+1): 552

Example 171(S,E)-N-(4-(4-(3-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 644

Example 172(S,E)-N-(4-(4-(3-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(PIPERIDIN-1-YL)-BUT-2-ENAMIDEMS (M+1): 656

Example 173(S,E)-N-(4-(4-(3-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(MORPHOLIN-4-YL)-BUT-2-ENAMIDEMS (M+1): 658

Example 174(E)-N-(4-(3-CHLORO-4-FLUOROPHENYLAMINO)-3-CYANO-7-(PYRIDIN-3-YL-OXY)QUINOLIN-6-YL)4-(DIMETHYLAMINO)-BUT-2-ENAMIDE

MS (M+1): 517.

The compound was prepared as hydrochloride according to the process ofExample 3 to determine, H¹-NMR (DMSO-d₆): δ 2.732 (s, 3H); 2.744 (s,3H); 3.945 (t, 2H, J₁=6.0); 3.955-4.097 (m, 5H); 6.784-6.989 (m, 2H);7.544-7.621 (m, 3H); 7.781-7.853 (m, 2H); 8.029 (dd, 1H, J₁=1.6,J₂=8.8); 8.695 (d, 1H, J=4.8); 8.773 (d, 1H, J=2.8); 9.079 (s, 1H);9.346 (s, 1H); 10.739 (s, 1H); 11.428 (br, 1H).

Example 175(E/Z)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 600

Example 176(E/Z)-N-(4-(3-CHLORO-4-FLUOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 510

Example 177(E/Z)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 482

Example 178(E/Z)-N-(4-(4-(BENZYLOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 564

Example 179(E/Z)-N-(4-(3-BROMOPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 536

Example 180(E/Z)-N-(4-(4-(3-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 616

Example 181(S,E/Z)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 510

Example 182(S,E/Z)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(PIPERIDIN-1-YL)-BUT-2-ENAMIDEMS (M+1): 522

Example 183(S,E/Z)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(MORPHOLIN-4-YL)-BUT-2-ENAMIDEMS (M+1): 524

Example 184(S,E/Z)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 627

Example 185(S,E/Z)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(PIPERIDIN-1-YL)-BUT-2-ENAMIDEMS (M+1): 629

Example 186(S,E/Z)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(MORPHOLIN-4-YL)-BUT-2-ENAMIDEMS (M+1): 641

Example 187(S,E/Z)-N-(4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-3-CYANO-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(2-METHOXYETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 629

Example 188(S,E)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIETHANOLAMINO)-BUT-2-ENAMIDEMS (M+1): 542

Example 189(S,E)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(N-METHYLMETHOXYETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 526

Example 190(S,E)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(N-METHYLETHANOLAMINO)-BUT-2-ENAMIDEMS (M+1): 512

Example 191(S,E)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHOXYETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 570

Example 192(S,E)-N-(3-CYANO-4-(3-CHLORO-4-FLUORO-PHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIETHANOLAMINO)-BUT-2-ENAMIDEMS (M+1): 570

Example 193(S,E)-N-(3-CYANO-4-(3-CHLORO-4-FLUORO-PHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(N-METHYLMETHOXYETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 554

Example 194(S,E)-N-(3-CYANO-4-(3-CHLORO-4-FLUORO-PHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(N-METHYLETHANOLAMINO)-BUT-2-ENAMIDEMS (M+1): 540

Example 195(S,E)-N-(3-CYANO-4-(3-CHLORO-4-FLUORO-PHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHOXYETHYLAMINO)-BUT-2-ENAMIDEMS (M+1): 598

Example 196(S,E)-N-(3-CYANO-4-(4-(3-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIETHANOLAMINO)-BUT-2-ENAMIDE MS (M+1): 676

Example 197(S,E)-N-(3-CYANO-4-(4-(3-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(N-METHYLMETHOXYETHYLAMINO)-BUT-2-ENAMIDE MS (M+1): 660

Example 198(S,E)-N-(3-CYANO-4-(4-(3-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(N-METHYLETHANOLAMINO)-BUT-2-ENAMIDE MS (M+1): 646

Example 199(S,E)-N-(3-CYANO-4-(4-(3-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHOXYETHYLAMINO)-BUT-2-ENAMIDE MS (M+1): 704

Example 200(S,E)-N-(3-CYANO-4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIETHANOLAMINO)-BUT-2-ENAMIDEMS (M+1): 589

Example 201(S,E)-N-(3-CYANO-4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(N-METHYLMETHOXYETHYLAMINO)-BUT-2-ENAMIDE MS (M+1): 643

Example 202(S,E)-N-(3-CYANO-4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(N-METHYLETHANOLAMINO)-BUT-2-ENAMIDE MS (M+1): 639

Example 203(S,E)-N-(3-CYANO-4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-7-(TETRAHYDROFUTAN-3-YL-OXY)QUINOLIN-6-YL)-4-(DIMETHOXYETHYLAMINO)-BUT-2-ENAMIDE MS (M+1): 687

Example 204(S,E)-N-(3-CYANO-4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(6-HYDROXYHEXYLAMINO)-BUT-2-ENAMIDE MS (M+1): 671

Example 205(S,E)-N-(3-CYANO-4-(3-CHLORO-4-FLUORO-PHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(6-HYDROXYHEXYLAMINO)-BUT-2-ENAMIDEMS (M+1). 582

Example 206(S,E)-N-(3-CYANO-4-(4-(3-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(6-HYDROXYHEXYLAMINO)-BUT-2-ENAMIDEMS (M+1): 688

Example 207(S,E)-N-(3-CYANO-4-(3-ETHYNYLPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(N-METHYL-6-AMINO-1-HEXANOLYL)-BUT-2-ENAMIDEMS (M+1): 566

(S,E)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(6-amino-1-hexanolyl)-but-2-enamide (552 mg, 0.001 mol) wasdissolved in DMF (15 ml). The solution was stirred homogeneously. To thesolution were added methyl iodide (156 mg (1.1 mmol), anhydrouspotassium carbonate (276 mg, 2 mmol) and tetrabutyl ammonium iodide (11mg, 0.03 mmol). The resulting mixture was stirred in the dark at theroom temperature. After 48 hr, the reaction was stopped. The reactionsolution was added into saturated sodium bicarbonate (150 ml). Themixture was extracted with ethyl acetate (150 ml) once. The organicphase was retained. Anhydrous magnesium sulfate was added into theorganic phase for half-hour. After half-hour, the drying agent wasremoved. The organic phase was concentrated in vacuo to give a yellowsolid. The solid was purified with column chromatography (eluent:chloroform:methanol=9:1) to give a yellow solid (342 mg). Yield: 60.5%.

The compounds of Examples 208-210 were prepared according to the processof Example 207.

Example 208(S,E)-N-(3-CYANO-4-(3-CHLORO-4-FLUORO-PHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(N-METHYL-6-AMINO-1-HEXANOLYL)-BUT-2-ENAMIDEMS (M+1): 596

Example 209(S,E)-N-(3-CYANO-4-(4-(3-FLUOROBENZYLOXY)-3-CHLOROPHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(N-METHYL-6-AMINO-1-HEXANOLYL)-BUT-2-ENAMIDEMS (M+1): 702

Example 210(S,E)-N-(3-CYANO-4-(3-CHLORO-4-(PYRIDIN-2-YL-METHOXY)PHENYLAMINO)-7-(TETRAHYDROFURAN-3-YL-OXY)QUINOLIN-6-YL)-4-(N-METHYL-6-AMINO-1-HEXANOLYL)-BUT-2-ENAMIDEMS (M+1): 485

BIOLOGICAL EXAMPLES

Abbreviations used in the following Biological Examples are as follows:EGFR-TK: intracellular epidermal growth factor receptor phosphorylase;A431 (human epithelial gland cancer cell strain); A549: human lungcancer cell strain; LoVo: human intestinal cancer cell strain; NCI-H460:human large cell lung cancer cell strain; NCI-N87: human gastric cancercell strain; Sk-Br-3: human breast cancer cell strain; SW620: humancolorectal cancer cell strain; BT-474: human breast cancer cell strain;CCRF-CEM/T: human acute lymphocytic cell leukemia cell resistant topaclitaxel; Fadu: human head and neck cancer cell strain; BxPC-3: humanpancreatic cancer cell strain; AsPC-1: human pancreatic cancer cellstrain; SK-OV-3: human ovarian cancer cell strain; NCI-H358: humannon-small cell lung cancer cell strain; NCI-H1650: human non-small celllung cancer cell strain; MDA-MB-453: human breast cancer cell strain;PGT: polyglutamic acid tyrosine; PBS: phosphate buffer, pH 7.4; ATP:triphosadenine; TKB: tyrosine kinase reaction buffer; SDS: sodiumdodecyl sulfate; PBST: PBS containing 0.05% Tween 20; BSA: bovine serumalbumin; HRP: horseradish peroxidase; TMB: 3,3′,5,5′-tetramethylbenzidine; DTT: dithiothreitol; ddH₂O: double distilled water; MTT:tetrazole; DMEM: Dulbecco's Modified Eagle's Medium; F12: F-12 NutrientMixture (Ham); EDTA: ethylene diamine tetraacetic acid; RPMI-1640:RPMI-1640 Medium; FBS: fetal bovine serum; SRB: sulforhodamine; Tris:trihydroxy methyl amino methane; EMEM: Minimum Essential Medium withEarle's salts; NEAA: non-essential amino acid; McCoy's 5A: McCoy's 5AMedium; HEPEs: hydroxyethylpiperazine ethanesulfonic acids; DMSO:dimethyl sulfoxide.

BIOLOGICAL EXAMPLE 1 A431 Cell Growth Inhibition Test (MTT Assay) I.Assay Materials

1. Cell strains: A431 (human epithelial adenocarcinoma cell strains);

2. MTT; antitumor compounds; DMSO

II. Reagents and Consumable Materials

Culture medium: 45% DMEM, 45% F12+10% FBS;

Pancreatin (0.25% (w/v) solution was formulated with PBS, 0.53 mM ofEDTA was added in the formulation);

PBS;

96-well culture plate

III. Assay Process

1. A plate (10 cm) of cells in logarithmic growth phase normallycultured was collected;

2. The culture solution was sucked out. The plate was washed with 5 mlof PBS 1-2 times;

3. PBS was sucked out, and 2 ml of 0.25% pancreatin was added toinfiltrate the cells for 1 min;

4. The pancreatin was sucked out, and the culture plate was placed in anincubator. Digestion was carried out for about 15 min at 37° C.;

5. 4 ml of complete culture solution was added in the culture plate tostop the digestion. The cells were carefully scoured with micropipette(1 ml) to give a uniform cell suspension. The suspension was implantedinto a 96-well cell culture plate by 2500 cells/100 μl per well. Theculture plate was incubated overnight under 5% CO₂ at 37° C. In day 2,100 μl of culture solution comprising the compound was added in eachwell, and further incubated for 68 h under 5% CO₂ at 37° C.

6. The culture solution was sucked out;

7. 100 μl of serum-free culture solution containing 0.5 mg/ml MTT wasadded in each well, and incubated for 4 h;

8. The culture solution was carefully sucked out;

9. 100 μl of DMSO was added into each well and vibrated to dissolve;

10. OD values were determined at 490 nM.

IV. Results and Treatments

1. Calculation of Relative Inhibition Ratio

The inhibition ratio of a compound on cell growth=(PC−n)/(PC−NC)×100%

wherein:

PC: OD value of cells after normal growth in control wells without acompound;

n: OD value of cells after growth in test wells with a compound;

NC: Background OD value of blank wells without a compound and cells;

IC₅₀: concentration of a compound where inhibition ratio was 50%. IC₅₀values were fitted with Origin7.5.

TABLE 1 Growth Inhibition Ratio of Some Compounds (1 μM) in Examples onA431 Cells Growth Growth Inhi- Inhi- Growth bition bition InhibitionRatio Ratio Compound Ratio (%) Compound (%) Compound (%) Example 3 85Example 4 80 Example 5 85 Example 8 91 Example 9 90 Example 13 89Example 15 91 Example 138 89 Example 139 90 Example 140 87 Example 14180 Example 142 75 Example 143 70 Example 150 84 Example 155 82 Example157 72 Example 158 77 Example 166 69 Example 167 75 Example 176 79Example 177 81 Example 180 73 Example 185 70 Example 190 79

TABLE 2 Growth Inhibition Activity (IC₅₀) of Some Compounds in Exampleson A431 Cells IC₅₀ Compounds IC₅₀ (μM) Compounds IC₅₀ (μM) Compounds(μM) Example 4 0.068 Example 5 0.024 Example 7 0.160 Example 8 0.145Example 9 0.135 Example 10 0.222 Example 11 0.184 Example 12 0.147Example 13 0.158 Example 174 0.95 Example 15 0.37 Example 16 0.358Example 17 0.194 Example 19 0.39 Example 21 0.081 Example 138 0.062Example 139 0.093 Example 140 0.026 Example 141 0.050 Example 142 0.045Example 143 0.059 Example 144 0.026 Example 145 0.071 Example 146 0.053Example 149 0.089 Example 150 0.027 Example 151 0.061 Example 152 0.062Example 153 0.053 Example 154 0.162

Biological Example 2 BT-474 Cell Growth Inhibition Test (SRB Assay) I.Assay Materials

1. Cell strains: BT-474 (human breast tumor cell strains);

2. SRB: available from Sigmaaldrich, goods number: S9012, lot number:047K3751. SRB was reserved at the room temperature. 0.4% (w/v) ofworking solution was formulated with 1% of glacial acetic acid. Thesolution was reserved at the temperature of 4° C.; anti-tumor compounds;DMSO.

II. Reagents and Consumable Materials

Culture medium (90% EMEM+10% FBS+0.1 mM NEAA, reserved at 4° C.);

Pancreatin (0.25% (w/v) solution was formulated with PBS, 0.53 mM ofEDTA was added in the formulation);

PBS;

FBS (fetal bovine serum);

Tris;

Glacial acetic acid;

96-well cell culture plate

III. Assay Process

1. A plate (10 cm) of cells in logarithmic growth phase normallycultured was collected. The culture solution was sucked out. The platewas washed with 5 mL of PBS 1-2 times;

2. PBS was sucked out, and 1.5 m of 0.25% pancreatin was added toinfiltrate the cells for 30 s;

3. The pancreatin was sucked out. The culture plate was pleaced in anincubator. Digestion was carried out for about 5 min at 37° C.;

4. 3 mL of complete culture solution was added to the culture plate tostop the digestion. The cells were carefully scoured with micropipette(1 ml) to give a uniform single cell suspension;

5. Cell suspension was counted. The suspension was diluted to 1×10⁵/ml.The resulting suspension was developed uniformly on a plate. The platewas incubated under 5% CO₂ at 37° C. overnight. In day 2, 80 μL ofcomplete culture medium was added in each well and then 20 μL of culturesolution comprising a compound was added. The mixture was incubated for70 h under 5% CO₂ at 37° C.

6. The culture solution was sucked out. 100 uL of TCA fixed cells whichwere diluted to 10% were added to each well. The plate was kept in arefrigerator for 1 h at 4° C.

7. TCA stationary liquid was sucked out. Each well was washed with 150μL of ddH₂O five times;

8. After the stationary liquid was cleansed, the plate was dried in theair at the room temperature;

9. 60 μL of SRB staining solution was added in each well. The well wasstained for 15 min at the room temperature;

10. The SRB staining solution was sucked out. Each well was washed with150 μL of 1% glacial acetic acid five times;

11. After the SRB staining solution was cleansed, the plate was dried inthe air at the room temperature;

12. 100 μL of 10 mM Tris was added in each well. The plate was vibratedto dissolve out SRB;

13. OD values were determined at 570 nM.

IV. Assay Results

1. Calculation of Relative Inhibition Ratio

The inhibition ratio of a compound on cell growth=(PC−n)/(PC−NC)×100%

wherein:

PC: OD value of cells after normal growth in control wells without acompound;

n: OD value of cells after growth in test wells with a compound;

NC: Background OD values of blank wells without a compound and cells;

IC₅₀: Concentration of a compound where inhibition ratio was 50%. IC₅₀values were fitted with Origin7.5.

TABLE 3 Growth Inhibition Ratio of Some Compounds (1 μM) in Examples onBT-474 Cells Growth Growth Inhi- Inhi- Growth bition bition InhibitionRatio Ratio Compounds Ratio (%) Compounds (%) Compounds (%) Example 4 79Example 5 85 Example 8 79 Example 9 78 Example 13 75 Example 15 71Example 16 72 Example 138 82 Example 139 81 Example 140 85 Example 14189 Example 142 89 Example 143 87 Example 145 75 Example 147 75 Example149 79 Example 150 82 Example 151 80 Example 152 78 Example 156 70Example 158 82 Example 162 80 Example 166 69 Example 167 75 Example 16886 Example 169 80 Example 171 84 Example 172 62 Example 173 67 Example176 89 Example 177 87 Example 180 78 Example 181 87 Example 183 75Example 184 83 Example 186 80 Example 189 85 Example 192 85 Example 19878 Example 201 80 Example 203 82 Example 205 75

TABLE 4 Growth Inhibition Activity (IC₅₀) of Some Compounds in Exampleson BT-474 Cells IC₅₀ IC₅₀ Compounds IC₅₀ (μM) Compounds (μM) Compounds(μM) Example 4 0.140 Example 5 0.041 Example 7 0.309 Example 9 0.0052Example 10 0.0099 Example 11 0.0079 Example 12 0.008 Example 13 0.011Example 189 0.108 Example 15 0.0081 Example 16 0.035 Example 17 0.017Example 19 0.032 Example 190 0.267 Example 21 0.0036 Example 138 0.003Example 139 0.0039 Example 140 0.033 Example 141 0.096 Example 142 0.133Example 143 0.149 Example 144 0.129 Example 145 0.654 Example 146 0.236Example 149 0.212 Example 150 0.0049 Example 151 0.0065 Example 1520.0104 Example 153 0.0072 Example 154 0.012 Example 191 0.390

Biological Example 3 A549 Cell Growth Inhibition Test (MTT Assay) I.Assay Materials

1. Cell strains: A4549 (human lung cancer cell strains);

2. MTT; antitumor compounds; DMSO.

II. Reagents and Consumable Materials

Culture medium: 90% F12K+10% FBS;

Pancreatin (0.25% (w/v) solution was formulated with PBS, 0.53 mM ofEDTA was added in the formulation);

PBS;

96-well culture plate

III. Assay Process

1. A plate (10 cm) of cells in logarithmic growth phase normallycultured was collected;

2. The culture solution was sucked out. The plate was washed with 5 mlof PBS 1-2 times;

3. PBS was sucked out. 2 ml of 0.25% pancreatin was added to infiltratethe cells for 1 min;

4. The pancreatin was sucked out. The culture plate was placed in anincubator. Digestion was carried out for about 2 min at 37° C.;

5. 4 ml of complete culture solution was added to the culture plate tostop the digestion. The cells were carefully scoured with micropipette(1 ml) to give a uniform cell suspension. The suspension was implantedinto a 96-well cell culture plate by 2500 cells/100 μl per well. Theculture plate was incubated overnight under 5% CO₂ at 37° C. In day 2,100 μl of culture solution comprising a compound was added in each well,and further incubated for 72 h under 5% CO₂ at 37° C.

6. The culture solution was sucked out;

7. 100 μl of serum-free culture solution containing 0.5 mg/ml MTT wasadded in each well, and incubated for 3 h;

8. The culture solution was carefully sucked out;

9. 100 μl of DMSO was added in each well and vibrated to dissolve;

10. OD values were determined at 490 nM.

IV. Results and Treatments

1. Calculation of Relative Inhibition Ratio

The inhibition ratio of a compound on cell growth=(PC−n)/(PC−NC)×100%

wherein:

PC: OD value of cells after normal growth in control wells without acompound;

n: OD value of cells after growth in test wells with s compound;

NC: Background OD value of blank wells without s compound and cells;

IC₅₀: Concentration of a compound where inhibition ratio was 50%. IC₅₀values were fitted with Origin7.5.

TABLE 5 Growth Inhibition Activity (IC₅₀) of Some Compounds in Exampleson A549 Cells IC₅₀ Compounds IC₅₀ (μM) Compounds IC₅₀ (μM) Compounds(μM) Example 4 1.25 Example 5 1.3 Example 7 3 Example 8 1.7 Example 91.7 Example 10 2.3 Example 11 1.6 Example 12 2 Example 13 1.1 Example 141.5 Example 15 3.9 Example 16 3.4 Example 17 2.4 Example 19 2 Example 210.9 Example 153 6.4 Example 138 1.5 Example 139 0.6 Example 140 1.6Example 141 0.8 Example 142 1.5 Example 143 1.5 Example 144 1 Example145 6.7 Example 146 7 Example 150 3.8 Example 151 3.7 Example 174 3.7

Biological Example 4 LoVo Cell Growth Inhibition Test (MTT Assay) I.Assay Materials

1. Cell strains: LoVo (human intestinal cancer cell strains);

2. MTT; antitumor compounds; DMSO.

II. Reagents and Consumable Materials

Culture medium: 90% RPMI-1640+10% FBS;

Pancreatin (0.25% (w/v) solution was formulated with PBS, and 0.53 mM ofEDTA was added in the formulation);

PBS;

96-well culture plate

III. Assay Process

1. A plate (10 cm) of cells in logarithmic growth phase normallycultured was collected;

2. The culture solution was sucked out. The plate was washed with 5 mlof PBS 1-2 times;

3. PBS was sucked out. 2 ml of 0.25% pancreatin was added to infiltratethe cells for 1 min;

4. The pancreatin was sucked out. The culture plate was placed in anincubator. Digestion was carried out for about 4 min at 37° C.;

5. 4 ml of complete culture solution was added in the culture plate tostop the digestion. The cells were carefully scoured with micropipette(1 ml) to give a uniform cell suspension. The suspension was implantedinto a 96-well cell culture plate by 3000-4000 cells/100 μl per well.The culture plate was incubated overnight under 5% CO₂ at 37° C. In day2, 100 μl of culture solution comprising a compound was added into eachwell, and further incubated for 72 h under 5% CO₂ at 37° C.

6. The culture solution was sucked out;

7. 100 μl of serum-free culture solution containing 0.5 mg/ml MTT wasadded in each well, and incubated for 4 h;

8. The culture solution was carefully sucked out;

9. 100 μl of DMSO was added in each well and vibrated to dissolve;

10. OD values were determined at 490 nM.

IV. Results and Treatments

1. Calculation of Relative Inhibition Ratio

The inhibition ratio of a compound on cell growth=(PC−n)/(PC−NC)×100%

wherein:

PC: OD value of cells after normal growth in control wells without acompound;

n: OD value of cells after growth in test wells with a compound;

NC: Background OD value of blank wells without a compound and cells;

IC₅₀: Concentration of a compound where inhibition ratio was 50%. IC₅₀values were fitted with Origin7.5.

TABLE 6 Growth Inhibition Activity (IC₅₀) of Some Compounds in Exampleson LoVo Cells IC₅₀ IC₅₀ IC₅₀ Compounds (μM) Compounds (μM) Compounds(μM) Example 4 8.0 Example 5 8.57 Example 7 7.0 Example 8 1.7 Example 91.58 Example 10 2.0 Example 11 1.6 Example 12 2.0 Example 13 2.0 Example14 1.3 Example 15 2.2 Example 16 1.8 Example 17 2.0 Example 19 2.0Example 21 2.0 Example 138 2.1 Example 139 2.2 Example 140 8.8 Example141 7.63 Example 142 8.83 Example 143 7.5 Example 144 3.3 Example 1535.6 Example 149 2.3 Example 150 2.2 Example 151 1.9 Example 152 6.6

Biological Example 5 NCI-H460 Cell Growth Inhibition Test (MTT Assay) I.Assay Materials

1. Cell strains: NCI-H460 (human large cell lung cancer cell strains);

2. MTT; antitumor compounds; DMSO

II. Reagents and Consumable Materials

Culture medium: 90% RPMI-1640+10% FBS;

Pancreatin (0.25% (w/v) solution was formulated with PBS, and 0.53 mM ofEDTA was added in the formulation);

PBS;

96-well culture plate

III. Assay Process

1. A plate (10 cm) of cells in logarithmic growth phase normallycultured was collected;

2. The culture solution was sucked out. The plate was washed with 5 mlof PBS 1-2 times;

3. PBS was sucked out. 2 ml of 0.25% pancreatin was added to infiltratethe cells for 1 min;

4. The pancreatin was sucked out. The culture plate was placed in anincubator. Digestion was carried out for about 2 min at 37° C.;

5. 4 ml of complete culture solution was added to the culture plate tostop the digestion. The cells were carefully scoured with micropipette(1 ml) to give a uniform cell suspension. The suspension was implantedinto a 96-well cell culture plate by 2500 cells/100 μl per well. Theculture plate was incubated overnight under 5% CO₂ at 37° C. In day 2,100 μl of culture solution comprising a compound was added in each well,and further incubated for 72 h under 5% CO₂ at 37° C.

6. The culture solution was sucked out;

7. 100 μl of serum-free culture solution containing 0.5 mg/ml MTT wasadded in each well, and incubated for 3 h;

8. The culture solution was carefully sucked out;

9. 100 μl of DMSO was added in each well and vibrated to dissolve;

10. OD values were determined at 490 nM.

IV. Results and Treatments

1. Calculation of Relative Inhibition Ratio

The inhibition ratio of a compound on cell growth=(PC−n)/(PC−NC)×100%

wherein:

PC: OD value of cells after normal growth in control wells without acompound;

n: OD value of cell after growth in test wells with a compound;

NC: Background OD values of blank wells without a compound and cells;

IC₅₀: Concentration of a compound where inhibition ratio was 50%. IC₅₀values were fitted with Origin7.5.

TABLE 7 Growth Inhibition Activity (IC₅₀) of Some Compounds in Exampleson NCI-H460 Cells IC₅₀ IC₅₀ IC₅₀ Compounds (μM) Compounds (μM) Compounds(μM) Example 4 1.6 Example 5 1.2 Example 7 0.94 Example 8 1.2 Example 91.7 Example 10 1.7 Example 11 1.5 Example 12 0.97 Example 13 1.8 Example14 0.94 Example 15 1.4 Example 16 1.1 Example 17 1.5 Example 19 1.1Example 21 2.7 Example 174 3.0 Example 46 4.0 Example 138 2.2 Example140 1.1 Example 141 2.9 Example 142 1.04

Biological Example 6 NCI-N87 Cell Growth Inhibition Test (MTT Assay) I.Assay Materials

1. Cell strains: NCI-N87 (human gastric carcinoma cell strains);

MTT; antitumor compounds; DMSO

II. Reagents and Consumable Materials

Culture medium: 90% RPMI-1640+10% FBS;

Pancreatin (0.25% (w/v) solution was formulated with PBS, and 0.53 mM ofEDTA was added in the formulation);

PBS;

96-well culture plate

III. Assay Process

1. A plate (10 cm) of cells in logarithmic growth phase normallycultured was collected;

2. The culture solution was sucked out. The plate was washed with 5 mlof PBS 1-2 times;

3. PBS was sucked out. 1.5 ml of 0.25% pancreatin was added toinfiltrate the cells for 1 min;

4. The pancreatin was sucked out. The culture plate was placed in anincubator. Digestion was carried out for about 12 min at 37° C.;

5. 4.5 ml of complete culture solution was added to the culture plate tostop the digestion. The cells were carefully scoured with micropipette(1 ml) to give a uniform cell suspension. The suspension was implantedinto a 96-well cell culture disc by 17000 cells/100 μl per well. Theculture plate was incubated overnight under 5% CO₂ at 37° C. In day 2,100 μl of culture solution comprising a compound was added in each well,and further incubated for 72 h under 5% CO₂ at 37° C.

6. The culture solution was sucked out;

7. 100 μl of serum-free culture solution containing 0.5 mg/ml MTT wasadded in each well, and incubated for 3 h;

8. The culture solution was carefully sucked out;

9. 100 μl of DMSO was added in each well and vibrated to dissolve;

10. OD values were determined at 490 nM.

IV. Results and Treatments

1. Calculation of Relative Inhibition Ratio

The inhibition ratio of a compound on cell growth=(PC−n)/(PC−NC)×100%

wherein:

PC: OD value of cells after normal growth in control wellswithout acompound;

n: OD value of cells after growth in test wellswith a compound;

NC: Background OD value of blank wellswithout a compound and cells;

IC₅₀: Concentration of a compound where inhibition ratio was 50%. IC₅₀values were fitted with Origin7.5.

TABLE 8 Growth Inhibition Activity (IC₅₀) of Some Compounds in Exampleson NCI-N87 Cells IC₅₀ IC₅₀ IC₅₀ Compounds (μM) Compounds (μM) Compounds(μM) Example 4 0.079 Example 5 0.022 Example 7 0.113 Example 8 0.0056Example 9 0.0086 Example 10 0.011 Example 11 0.011 Example 12 0.0061Example 13 0.0044 Example 153 0.015 Example 15 0.0071 Example 16 0.026Example 17 0.021 Example 19 0.032 Example 154 0.041 Example 21 0.0068Example 138 0.0044 Example 139 0.0072 Example 140 0.015 Example 1410.032 Example 142 0.075 Example 143 0.089 Example 144 0.098 Example 1450.346 Example 146 0.189 Example 149 0.111 Example 150 0.0066 Example 1510.016 Example 152 0.020

Biological Example 7 Sk-Br-3 Cell Growth Inhibition Test (SRB Assay) I.Assay Materials

1. Cell strains: Sk-Br-3 (human breast cancer cell strains);

2. SRB: available from Sigmaaldrich, goods number: S9012, lot number:047K3751. SRB was reserved at the room temperature. 0.4% (w/v) ofworking solution was formulated with 1% of glacial acetic acid. Thesolution was reserved at 4° C.; anti-tumor compounds; DMSO

II. Reagents and Consumable Materials

Culture medium: 90% DMEM+10% FBS;

Pancreatin (0.25% (w/v) solution was formulated with PBS, 0.53 mM ofEDTA was added in the formulation);

PBS;

Tris;

Glacial acetic acid;

96-well culture plate

III. Assay Process

1. A plate (10 cm) of cells in logarithmic growth phase normallycultured was collected. The culture solution was sucked out. The platewas washed with 5 mL of PBS 1-2 times;

2. PBS was sucked out. 1.5 m of 0.25% pancreatin was added to infiltratethe cells for 30 s;

3. The pancreatin was sucked out. The culture plate was placed in anincubator. Digestion was carried out for about 1.5-2 min at 37° C.;

4. 4 mL of complete culture solution was added to the culture plate tostop the digestion. The cells were carefully scoured with micropipette(1 ml) to give a uniform single cell suspension;

5. Cell suspension was counted. The suspension was diluted to 1×10⁵/ml.The resulting suspension was developed uniformly on a plate by 10000cells/100 μl per well. The culture plate was incubated overnight under5% CO₂ at 37° C. In day 2, 100 μl of culture solution comprising acompound was added in each well, and further incubated for 91 h under 5%CO₂ at 37° C.

6. The culture solution was sucked out. 100 uL of TCA fixed cells whichwere diluted to 10% were added to each well. The plate was kept in arefrigerator for 1 h at 4° C.

7. TCA stationary liquid was sucked out. Each well was washed with 150μL of ddH₂O five times;

8. After the stationary liquid was cleansed, the plate was dried in theair at the room temperature;

9. 60 μL of SRB staining solution was added in each well. The well wasstained for 15 min at the room temperature;

10. The SRB staining solution was sucked out. Each well was washed with150 μL of 1% glacial acetic acid five times;

11. After the SRB staining solution was cleansed, the plate was dried inthe air at the room temperature;

12. 100 μL of 10 mM Tris was added in each well. The plate was vibratedto dissolve out SRB;

13. OD values were determined at 570 nM.

IV. Results and Treatments

1. Calculation of Relative Inhibition Ratio

To: OD values of the starting content of cells when the cells weredeveloped on a plate;

PC: OD values of cells after normal growth in control wells without acompound;

Ti: OD values of cells after growth in test wells with a compound;

NC: Background OD values of blank well without a compound and cells

(1) If Ti>To, it shows that cells still grow after a compound was added.

Therefore:

Ratio of cells in test wells to normal wells (% of control cell growth)

=(Ti−To)/(PC−To)×100%

Ratio GI₅₀ was concentration of a compound at the point of 50%.

(2) If Ti<To, it shows that cells gradually die after a compound wasadded.

Therefore:

Ratio of killed cells to inoculated cells (% of killed cells)

=(Ti−To)/(To−NC)×100%

LC₅₀ was concentration point of a compound when half of the startinginoculated concentration was reached.

(3) If Ti=To, it shows that in the presence of a compound, both growthand death of cells tended to balance. Concentration of a compound atthis point is defined as TGI (total growth inhibition).

TABLE 9 Growth Inhibition Activity (GI₅₀) of Some Compounds in Exampleson Sk-Br-3 Cells GI₅₀ GI₅₀ GI₅₀ Compounds (μM) Compounds (μM) Compounds(μM) Example 4 0.148 Example 5 0.024 Example 7 0.213 Example 9 0.015Example 10 0.006 Example 14 0.924 Example 16 0.036 Example 17 0.007Example 19 0.063 Example 21 0.0041 Example 154 0.038 Example 138 0.0038Example 139 0.0052 Example 140 0.022 Example 141 0.039 Example 142 0.117Example 143 0.231 Example 144 0.202 Example 145 0.831 Example 146 0.823Example 149 0.644 Example 150 0.011 Example 151 0.017 Example 152 0.019Example 153 0.0068

Biological Example 8 SW620 Cell Growth Inhibition Test (SRB Assay) I.Assay Materials

Cell strains: SW620 (human colorectal cancer cell strains);

SRB: available from Sigmaaldrich, goods number: S9012, lot number:047K3751. RT was reserved at the room temperature. 0.4% (w/v) of workingsolution was formulated with 1% of glacial acetic acid. The solution wasreserved at 4° C.; anti-tumor compounds; DMSO.

II. Reagents and Consumable Materials

Culture medium: 90% L15+10% FBS;

Pancreatin (0.25% (w/v) solution was formulated with PBS, 0.53 mM ofEDTA was added in the formulation);

PBS;

Tris;

Glacial acetic acid;

96-well culture plate

III. Assay Process

1. A plate (10 cm) of cells in logarithmic growth phase normallycultured was collected. The culture solution was sucked out. The platewas washed with 5 mL of PBS 1-2 times;

2. PBS was sucked out. 1.5 m of 0.25% pancreatin was added to infiltratethe cells for 30 s;

3. The pancreatin was sucked out. The culture plate was placed in anincubator. Digestion was carried out for about 1.5-2 min at 37° C.;

4. 4 mL of complete culture solution was added to the culture plate tostop the digestion. The cells were carefully scoured with micropipette(1 ml) to give a uniform single cell suspension;

5. Cell suspension was counted. The suspension was diluted to1.5×10⁵/ml. The resulting suspension was developed uniformly on a plateby 15000 cells/100 μl per well. The culture plate was incubatedovernight under 5% CO₂ at 37° C. In day 2, 100 μl of culture solutioncomprising a compound was added in each well, and further incubated for91 h under 5% CO₂ at 37° C.;

6. The culture solution was sucked out. 100 uL of TCA fixed cells whichwere diluted to 10% were added to each well. The plate was kept in arefrigerator for 1 h at 4° C.

7. TCA stationary liquid was sucked out. Each well was washed with 150μL of ddH₂O five times;

8. After the stationary liquid was cleansed, the plate was dried in theair at the room temperature;

9. 60 μL of SRB staining solution was added in each well. The well wasstained for 15 min at the room temperature;

10. The SRB staining solution was sucked out. Each well was washed with150 μL of 1% glacial acetic acid five times;

11. After the SRB staining solution was cleansed, the plate was dried inthe air at the room temperature;

12. 100 μL of 10 mM Tris was added in each well, the plate was vibratedto dissolve out SRB;

13. OD values were determined at 570 nM.

IV. Results and Treatments

1. Calculation of Relative Inhibition Ratio

To: OD values of the starting content of cells when the cells weredeveloped on a plate;

PC: OD values of cells after normal growth in control wells without acompound;

Ti: OD values of cells after growth in test wells with a compound;

NC: Background OD values of blank wells without a compound and cells

(1) If Ti>To, it shows that cells still grow after a compound was added.

Therefore:

Ratio of cells in test wells to normal wells (% of control cell growth)

=(Ti−To)/(PC−To)×100%

Ratio GI₅₀ was concentration of a compound at the point of 50%.

(2) If Ti<To, it shows that cells gradually die after a compound wasadded.

Therefore:

Ratio of killed cells to inoculated cells (% of killed cell)

=(Ti−To)/(To−NC)×100%

LC₅₀ was concentration point of a compound when half of the startinginoculated concentration was reached.

(3) If Ti=To, it shows that in the presence of a compound, both growthand death of cells tended to balance. Concentration of a compound atthis point is defined as TGI (total growth inhibition).

TABLE 10 Growth Inhibition Activity (GI₅₀) of Some Compounds in Exampleson SW620 Cells GI₅₀ GI₅₀ GI₅₀ Compounds (μM) Compounds (μM) Compounds(μM) Example 4 3.5 Example 5 1.68 Example 9 2.1 Example 21 1.78 Example138 1.78 Example 139 1.9 Example 140 2.3 Example 141 1.4 Example 142 2.3

Biological Example 9 CCRF-CEM/T Cell Growth Inhibition Test (MTT Assay)I. Assay Materials

Cell strains: CCRF-CEM/T (human acute lymphocytic cell leukemia cells);

MTT; antitumor compounds; DMSO

II. Reagents and Consumable Materials

Culture medium: 90% RPMI-1640+10% FBS;

PBS;

96-well cell culture plate;

triple lysate solution: 10% SDS, 5% isobutanol, 0.012M HCl.

III. Assay Process

1. Cells were cultured to exponential phase. The cells were suspensioncells;

2. The cells were collected by centrifuge. The resulting cells wereresuspended in a complete culture medium to a desired concentration. Thecells suspension was implanted into a 96-well cell culture plate by20000 cells per well. A compound was added in the wellsuch that thefinal volume of the system was 120 al. The system was further incubatedfor 72 h under 5% CO₂ at 37° C.

7. 30 μl of serum-free culture solution containing 2.5 mg/ml MTT wasadded in each well, and incubated for 3 h;

8. 150 μl of triple lysate solution was added in each well and placed todissolve at the room temperature;

9. OD values were determined at 570 nM.

IV. Results and Treatments

1. Calculation of Relative Inhibition Ratio

The inhibition ratio of a compound on cell growth=(PC−n)/(PC−NC)×100%

wherein:

PC: OD values of cells after normal growth in control wells without acompound;

n: OD values of cells after growth in test wells with a compound;

NC: Background OD values of blank wells without a compound and cells;

IC₅₀: Concentration of a compound where inhibition ratio was 50%. IC₅₀values were fitted with Origin7.5.

TABLE 11 Growth Inhibition Activity (IC₅₀) of Some Compounds in Exampleson CCRF-CEM/T Cells IC₅₀ IC₅₀ IC₅₀ Compounds (μM) Compounds (μM)Compounds (μM) Example 2 1.8 Example 4 5.8 Example 5 9 Example 158 1.1Example 138 5.6 Example 139 1.4 Example 140 7.9 Example 141 9.1 Example142 6.6 Example 150 3.76 Example 151 3.6

Biological Example 10 Fadu Cell Growth Inhibition Test (MTT Assay) I.Assay Materials

Cell strains: Fudu (human head and neck cancer cell strains);

MTT; antitumor compounds; DMSO

II. Reagents and Consumable Materials

Culture medium: 90% EMEM+10% FBS;

Pancreatin (0.25% (w/v) solution was formulated with PBS, 0.53 mM ofEDTA was added in the formulation);

PBS;

96-well culture plate

III. Assay Process

1. A plate (10 cm) of cells in logarithmic growth phase normallycultured was collected;

2. The culture solution was sucked out. The plate was washed with 5 mlof PBS 1-2 times;

3. PBS was sucked out. 1.5 ml of 0.25% pancreatin was added toinfiltrate the cells for 1 min;

4. The pancreatin was sucked out. The culture plate was placed in anincubator. Digestion was carried out for about 5 min at 37° C.;

5. 4.5 ml of complete culture solution was added to the culture plate tostop the digestion. The cells were carefully scoured with micropipette(1 ml) to give a uniform cell suspension. The suspension was implantedinto a 96-well cell culture plate by 6000 cells/100 μl per well. Theculture plate was incubated overnight under 5% CO₂ at 37° C. In day 2,100 μl of culture solution comprising a compound was added in each well,and further incubated for 72 h under 5% CO₂ at 37° C.

6. The culture solution was sucked out;

7. 100 μl of serum-free culture solution containing 0.5 mg/ml MTT wasadded in each well, and incubated for 3 h;

8. The culture solution was carefully sucked out;

9. 100 μl of DMSO was added in each welland vibrated to dissolve;

10. OD values were determined at 490 nM.

IV. Results and Treatments

1. Calculation of Relative Inhibition Ratio

The inhibition ratio of a compound on cell growth=(PC−n)/(PC−NC)×100%

wherein:

PC: OD values of cells after normal growth in control wells without acompound;

n: OD values of cells after growth in test wells with a compound;

NC: Background OD values of blank wells without s compound and cells;

IC₅₀: Concentration of a compound where inhibition ratio was 50%. IC₅₀values were fitted with Origin7.5.

TABLE 12 Growth Inhibition Activity (IC₅₀) of Somes Compounds inExamples on Fadu Cells IC₅₀ IC₅₀ IC₅₀ Compounds (μM) Compounds (μM)Compounds (μM) Example 2 149 Example 4 331 Example 143 127 Example 7 474Example 8 188 Example 9 219 Example 11 187 Example 12 202 Example 13 300Example 15 260 Example 138 101 Example 139 201 Example 144 103 Example145 194 Example 146 200 Example 149 163 Example 150 207 Example 151 244Example 152 170 Example 153 231 Example 154 324 Example 142 115 Example158 119

Biological Example 11 BxPc-3 Cell Growth Inhibition Test (MTT Assay) I.Assay Materials

Cell strains: BxPC-3 (human pancreatic cancer cell strains);

MTT; antitumor compounds; DMSO

II. Reagents and Consumable Materials

Culture medium: 90% RPMI-1640+10% FBS;

Pancreatin (0.25% (w/v) solution was formulated with PBS, 0.53 mM ofEDTA was added in the formulation);

PBS;

96-well culture plate

III. Assay Process

1. A plate (10 cm) of cells in logarithmic growth phase normallycultured was collected;

2. The culture solution was sucked out. was added into The plate waswashed with 5 ml of PBS 1-2 times;

3. PBS was sucked out. 1.5 ml of 0.25% pancreatin was added toinfiltrate the cells for 1 min;

4. The pancreatin was sucked out. The culture plate was placed in anincubator. Digestion was carried out for about 5 min at 37° C.;

5. 4.5 ml of complete culture solution was added to the culture plate tostop the digestion. The cells were carefully scoured with micropipette(1 ml) to give a uniform cell suspension. The suspension was implantedinto a 96-well cell culture plate by 5000 cells/100 μl per well. Theculture plate was incubated overnight under 5% CO₂ at 37° C. In day 2,100 μl of culture solution comprising a compound was added in each well,and further incubated for 72 h under 5% CO₂ at 37° C.

6. The culture solution was sucked out;

7. 100 μl of serum-free culture solution containing 0.5 mg/ml MTT wasadded in each well, and incubated for 3 h;

8. The culture solution was carefully sucked out;

9. 100 μl of DMSO was added in each well and vibrated to dissolve;

10. OD values were determined at 490 nM.

IV. Results and Treatments

1. Calculation of Relative Inhibition Ratio

The inhibition ratio of a compound on cell growth=(PC−n)/(PC−NC)×100%

wherein:

PC: OD values of cells after normal growth in control wells without acompound;

n: OD values of cells after growth in test wells with a compound;

NC: Background OD values of blank wells without a compound and cells;

IC₅₀: Concentration of a compound where inhibition ratio was 50%. IC₅₀values were fitted with Origin7.5.

TABLE 13 Growth Inhibition Activity (IC₅₀) of Some Compounds in Exampleson BxPc-3 Cells IC₅₀ IC₅₀ IC₅₀ Compounds (μM) Compounds (μM) Compounds(μM) Example 131 306 Example 138 337 Example 139 188 Example 142 416

Biological Example 12 AsPC-1 Cell Growth Inhibition Test (MTT Assay) I.Assay Materials

Cell strains: AsPC-1 (human pancreatic cancer cell strains);

MTT; antitumor compounds; DMSO

II. Reagents and Consumable Materials

Culture medium: 90% RPMI-1640+10% FBS;

Pancreatin (0.25% (w/v) solution was formulated with PBS, 0.53 mM ofEDTA was added in the formulation);

PBS;

96-well culture plate

III. Assay Process

1. A plate (10 cm) of cells in logarithmic growth phase normallycultured was collected;

2. The culture solution was sucked out. The plate was washed with 5 mlof PBS 1-2 times;

3. PBS was sucked out. 1.5 ml of 0.25% pancreatin was added toinfiltrate the cells for 1 min;

4. The pancreatin was sucked out. The culture plate was placed in anincubator. Digestion was carried out for about 7.5 min at 37° C.;

5. 4.5 ml of complete culture solution was added to the culture plate tostop the digestion. The cells were carefully scoured with micropipette(1 ml) to give a uniform cell suspension. The suspension was implantedinto a 96-well cell culture plate by 8000 cells/100 μl per well. Theculture plate was incubated overnight under 5% CO₂ at 37° C. In day 2,100 μl of culture solution comprising a compound was added in each well,and further incubated for 72 h under 5% CO₂ at 37° C.

6. The culture solution was sucked out;

7. 100 μl of serum-free culture solution containing 0.5 mg/ml MTT wasadded in each well, and incubated for 3 h;

8. The culture solution was carefully sucked out;

9. 100 μl of DMSO was added in each welland vibrated to dissolve;

10. OD values were determined at 490 nM.

IV Results and Treatments

1. Calculation of Relative Inhibition Ratio

The inhibition ratio of a compound on cell growth=(PC−n)/(PC−NC)×100%

wherein:

PC: OD values of cells after normal growth in control wells without acompound;

n: OD values of cells after growth in test wells with a compound;

NC: Background OD values of blank wells without a compound and cells;

IC₅₀: Concentration of a compound where inhibition ratio was 50%. IC₅₀values were fitted with Origin7.5.

TABLE 14 Growth Inhibition Activity (IC₅₀) of Some Compounds in Exampleson AsPC-1 Cells IC₅₀ IC₅₀ IC₅₀ Compounds (μM) Compounds (μM) Compounds(μM) Example 2 0.77 Example 4 1 Example 142 1.5 Example 150 0.895Example 8 0.878 Example 9 0.458 Example 11 1.2 Example 12 1.2 Example 130.922 Example 14 1.4 Example 15 1.1 Example 16 0.81 Example 17 1 Example19 0.621 Example 10 1 Example 138 1 Example 139 0.422 Example 151 0.81Example 158 0.44

Biological Example 13 SK-OV-3 Cell Growth Inhibition Test (MTT Assay) I.Assay Materials

Cell strains: SK-OV-3 (human ovarian cancer cell strains);

MTT; antitumor compounds; DMSO.

II. Reagents and Consumable Materials

Culture medium: 90% McCoy's 5A+10% FBS;

Pancreatin (0.25% (w/v) solution was formulated with PBS, 0.53 mM ofEDTA was added in the formulation);

PBS;

96-well culture plate

III. Assay Process

1. A plate (10 cm) of cells in logarithmic growth phase normallycultured was collected;

2. The culture solution was sucked out. The plate was washed with 5 mlof PBS 1-2 times;

3. PBS was sucked out. 1.5 ml of 0.25% pancreatin was added toinfiltrate the cells for 1 min;

4. The pancreatin was sucked out. The culture plate was placed in anincubator. Digestion was carried out for about 5 min at 37° C.;

5. 4.5 ml of complete culture solution was added to the culture plate tostop the digestion. T the cells were carefully scoured with micropipette(1 ml) to give a uniform cell suspension. The suspension was implantedinto a 96-well cell culture disc by 4000 cells/100 μl per well. Theculture plate was incubated overnight under 5% CO₂ at 37° C. In day 2,100 μl of culture solution comprising a compound was added in each well,and further incubated for 72 h under 5% CO₂ at 37° C.

6. The culture solution was sucked out;

7. 100 μl of serum-free culture solution containing 0.5 mg/ml MTT wasadded in each well, and incubated for 3 h;

8. The culture solution was carefully sucked out;

9. 100 μl of DMSO was added in each well and vibrated to dissolve;

10. OD values were determined at 490 nM.

IV. Results and Treatments

1. Calculation of Relative Inhibition Ratio

The inhibition ratio of a compound on cell growth=(PC−n)/(PC−NC)×100%

wherein:

PC: OD values of cells after normal growth in control wells without acompound;

n: OD values of cells after growth in test wellswith a compound;

NC: Background OD values of blank wells without a compound and cells;

IC₅₀: Concentration of a compound where inhibition ratio was 50%. IC₅₀values were fitted with Origin7.5.

TABLE 15 Growth Inhibition Activity (IC₅₀) of Some Compounds in Exampleson SK-OV-3 Cells IC₅₀ IC₅₀ IC₅₀ Compounds (μM) Compounds (μM) Compounds(μM) Example 2 331 Example 4 409 Example 5 195 Example 9 469 Example 138457 Example 139 371 Example 140 286 Example 141 283 Example 142 553Example 189 312

Biological Example 14 NCI-H358 Cell Growth Inhibition Test (MTT Assay)I. Assay Materials

Cell strains: NCI-H358 (human non-small cell lung cancer cell strains);

MTT; antitumor compounds; DMSO

II. Reagents and Consumable Materials

Culture medium: 90% RPMI-1640+10% FBS;

Pancreatin (0.25% (w/v) solution was formulated with PBS, 0.53 mM ofEDTA was added in the formulation);

PBS;

96-well culture plate

III. Assay Process

1. A plate (10 cm) of cells in logarithmic growth phase normallycultured was collected;

2. The culture solution was sucked out. The plate was washed with 5 mlof PBS 1-2 times;

3. PBS was sucked out. 1.5 ml of 0.25% pancreatin was added toinfiltrate the cells for 1 min;

4. The culture plate was placed in an incubator. Digestion was carriedout for about 5 min at 37° C.;

5. 3 ml of complete culture solution was added to the culture plate tostop the digestion. The cells were carefully scoured with micropipette(1 ml) to give a uniform cell suspension. The suspension was implantedinto a 96-well cell culture plate by 10000 cells/100 μl per well. Theculture plate was incubated overnight under 5% CO₂ at 37° C. In day 2,100 μl of culture solution comprising a compound was added in each well,and further incubated for 72 h under 5% CO₂ at 37° C.

6. The culture solution was sucked out;

7. 100 μl of serum-free culture solution containing 0.5 mg/ml MTT wasadded in each well, and incubated for 3 h;

8. The culture solution was carefully sucked out;

9. 100 μl of DMSO was added in each well and vibrated to dissolve;

10. OD values were determined at 490 nM.

IV. Results and Treatments

1. Calculation of Relative Inhibition Ratio

The inhibition ratio of a compound on cell growth=(PC−n)/(PC−NC)×100%

wherein:

PC: OD values of cells after normal growth in control wells without acompound;

n: OD values of cells after growth in test wells with a compound;

NC: Background OD values of blank wells without a compound and cells;

IC₅₀: Concentration of a compound where inhibition ratio was 50%. IC₅₀values were fitted with Origin7.5.

TABLE 16 Growth Inhibition Activity (IC₅₀) of Some Compounds in Exampleson NCI-H358 Cells IC₅₀ IC₅₀ IC₅₀ Compounds (μM) Compounds (μM) Compounds(μM) Example 138 54 Example 153 78 Example 188 110

Biological Example 15 NCI-H1650 Cell Growth Inhibition Test (SRB Assay)I. Assay Materials

1. Cell strains: NCI-H1650 (human non-small cell lung cancer cellstrains);

2. SRB, 0.4% (w/v) working solution was formulated with 1% glacialacetic acid and reserved at 4° C.; antitumor compounds; DMSO

II. Reagents and Consumable Materials

Culture medium: 90% RPMI1640+10% FBS;

Pancreatin (0.25% (w/v) solution was formulated with PBS, 0.53 mM ofEDTA was added in the formulation);

PBS;

Tris;

Glacial acetic acid;

96-well culture plate

III. Assay Process

1. A plate (10 cm) of cells in logarithmic growth phase normallycultured was collected;

2. The culture solution was sucked out. The plate was washed with 5 mLof PBS 1-2 times;

3. 1.5 mL of 0.25% pancreatin was added to the plate to infiltrate thecells;

4. The pancreatin was sucked out. The culture plate was placed in anincubator. Digestion was carried out for about 3 min at 37° C.;

5. 4 mL of complete culture solution was added to the culture plate tostop the digestion. The cells were carefully scoured with micropipette(1 ml) to give a uniform single cell suspension. The suspensin wasimplanted into a 96-well cell culture plate by 6000 cells/100 μl perwell. The culture plate was incubated overnight under 5% CO₂ at 37° C.In day 2, 100 μl of culture solution comprising a compound was added ineach well, and further incubated for 72 h under 5% CO₂ at 37° C.;

6. The culture solution was sucked out. 100 uL of TCA fixed cells whichwere diluted to 10% were added to each well. The plate was kept in arefrigerator for 1 h at 4° C.

7. TCA stationary liquid was sucked out. Each well was washed with 150μL of ddH₂O five times;

8. After the stationary liquid was cleansed, the plate was dried in theair at the room temperature;

9. 60 μL of SRB staining solution was added in each well. The well wasstained for 15 min at the room temperature;

10. The SRB staining solution was sucked out. Each well was washed with150 μL of 1% glacial acetic acid five times;

11. After the SRB staining solution was cleansed, the plate was dried inthe air at the room temperature; 12. 100 μL of 10 mM Tris was added ineach well, the plate was vibrated to dissolve out SRB;

13. OD values were determined at 570 nM.

IV. Results and Treatments

1. Calculation of Relative Inhibition Ratio

The inhibition ratio of a compound on cell growth=(PC−n)/(PC−NC)×100%

wherein:

PC: OD values of cells after normal growth in control wells without acompound;

n: OD values of cells after growth in test wells with a compound;

NC: Background OD values of blank wells without a compound and cells;

IC₅₀: Concentration of a compound where inhibition ratio was 50%. IC₅₀values were fitted with Origin7.5.

TABLE 17 Growth Inhibition Activity (IC₅₀) of Some Compounds in Exampleson NCI-H1650 Cells IC₅₀ IC₅₀ IC₅₀ Compounds (μM) Compounds (μM)Compounds (μM) Example 9 636 Example 138 1100 Example 139 1130 Example 3819 Example 158 760

Biological Example 16 MDA-MB-453 Cell Growth Inhibition Test (SRB Assay)I. Assay Materials

Cell strains: MDA-MB-453 (human breast cancer cell strains);

SRB: 0.4% (w/v) working solution was formulated with 1% glacial aceticacid, reserved at 4° C.; antitumor compounds; DMSO

II. Reagents and Consumable Materials

Culture medium: 90% L15+10% FBS;

pancreatin (0.25% (w/v) solution was formulated with PBS, 0.53 mM ofEDTA was added in the formulation);

PBS;

96-well culture plate

III. Assay Process

1. A plate (10 cm) of cells in logarithmic growth phase normallycultured was collected;

2. The culture solution was sucked out. The plate was washed with 5 mLof PBS 1-2 times;

3. 1.5 mL of 0.25% pancreatin was added to the plate to infiltrate thecells;

4. The pancreatin was sucked out. The culture plate was placed in anincubator. Digestion was carried out for about 3 min at 37° C.;

5. 4 mL of complete culture solution was added to the culture plate tostop the digestion. The cells were carefully scoured with micropipette(1 ml) to give a uniform single cell suspension. The suspension wasimplanted into a 96-well cell culture plate by 7000 cells/100 μl perwell. The culture plate was incubated overnight under 5% CO₂ at 37° C.In day 2, 100 μl of culture solution comprising a compound was added ineach well, and further incubated for 72 h under 5% CO₂ at 37° C.;

6. The culture solution was sucked out. 100 uL of TCA fixed cells whichwere diluted to 10% were added to each well. The plate was kept in arefrigerator for 1 h at 4° C.

7. TCA stationary liquid was sucked out. Each well was washed with 150μL of ddH₂O five times;

8. After the stationary liquid was cleansed, the plate was dried in theair at the room temperature;

9. 60 μL of SRB staining solution was added in each well. The well wasstained for 15 min at the room temperature;

10. The SRB staining solution was sucked out. Each well was washed with150 μL of 1% glacial acetic acid five times;

11. After the SRB staining solution was cleansed, the plate was dried inthe air at the room temperature;

12. 100 μL of 10 mM Tris was added in each well. The plate was vibratedto dissolve out SRB;

13. OD values were determined at 570 nM.

IV. Results and Treatments

1. Calculation of Relative Inhibition Ratio

The inhibition ratio of a compound on cell growth=(PC−n)/(PC−NC)×100%

wherein:

PC: OD values of cells after normal growth in control wells without acompound;

n: OD values of cells after growth in test wells with a compound;

NC: Background OD values of blank wells without a compound and cells;

IC₅₀: Concentration of a compound where inhibition ratio was 50%. IC₅₀values were fitted with Origin7.5.

TABLE 18 Growth Inhibition Activity (IC₅₀) or Some Compounds in Exampleson MDA-MB-453 Cells IC₅₀ IC₅₀ Compounds (μM) Compounds (μM) Example 5505 Example 189 523

Biological Example 17 Inhibition Test on EGFR-TK I. Operation Procedures

1. 2 mg/ml of PGT was diluted with PBS to 0.2 mg/ml. The resultingsolution was added into elisa plate by 50 μl per well. The plate wasplaced in a refrigerator at 4° C. and coated overnight.

2. The coating solution was discarded to stop coating. The plate waswashed three times with PBS, and then beaten to dryness.

3. The elisa plate was placed in a refrigerator at 4° C., drained outand stood for 2 h.

4. The mother liquid of aqueous solution of each compound was dilutedwith double distilled water to four folds, i.e. a desirableconcentration. Then, the compound was diluted and added in thecorresponding elisa well by 25 μl/well.

5. 4 nM of ATP solution was diluted with double distilled water to 50folds and then sufficiently mixed. The resulting solution was separatelyadded in each elisa well by 25 μl per well (except for the negativecontrol).

6. EGFR kinase was diluted with 2×TKB to 800 folds. The solution wasadded in elisa well with 50 μl per well. Then, the enzyme reactionbegan. The elisa plate was immediately placed on a micro-oscillator andshaked to react for 20 min at the room temperature.

7. 2% of SDS was added in the elisa well to stop the reaction by adding100 μl of SDS into each well. The solution was sufficiently mixed on themicro-oscillator to sufficiently mix for about 5 min.

8. The reaction solution was sucked out. The plate was washed four timeswith PBST. After the plate was beaten to dryness, 0.25 μg/ml of miceanti-phosphorylation tyrosine-HRP antibody which was diluted withblocking solution (3% solution of BSA in PBST) was added in the plate by100 μl per well. The mixture was reacted for 30 min at the roomtemperature.

9. The antibody reaction solution was sucked out. The plate was washedfour times with PBST. After the plate was beated to dryness, TMBperoxidase substrate was added to the plate by 100 μl/well. The mixturereacted in the dark for 15 min at the room temperature.

10. 100 μl of 2N H₂SO₄ was added in the plate to stop the chromogenicreaction. After the bubbles were cleansed, OD values were determined inELIASA at 450 nm.

11. Formula for calculating inhibition percentage:

${{Inhibition}\mspace{14mu} \%} = {100 - {\frac{{Reading}\mspace{14mu} {of}\mspace{14mu} {Infrared}\mspace{14mu} {Reader}\mspace{14mu} ({Drug})}{{Reading}\mspace{14mu} {of}\mspace{14mu} {Infrared}\mspace{14mu} {Reader}\mspace{14mu} ({Blank})} \times 100}}$

EC₅₀ values of some compounds were given in Table 1.

TABLE 19 Inhibition Activity (EC₅₀) of Some Compounds in Examples onEGFR-TK phosphorylation EC₅₀ EC₅₀ EC₅₀ Compounds (μM) Compounds (μM)Compounds (μM) Example 4 42 Example 5 44 Example 9 135 Example 46 25Example 138 110 Example 21 154

Biological Example 18 Inhibition Activity Assay on Her2 Enzyme I. AssayMaterials

1. Her2 kinase, Cell Signaling Tech, #7382, Lot. 2, reserved at −80° C.;

2. Elisa plate, Nunc Maxisorp, 442404;

3. Test compounds and control compounds were prepared by applicants;

II. Assay Reagemts

1. PBS: 8 g/L NaCl, 0.2 g/L KCl, 2.9 g/L Na₂HPO₄ 12H₂O, 0.2 g/L KH₂PO₄;

2. PBST: PBS+0.05% (v/v) Tween 20;

3. Confining liquid: 3% of BSA in PBS; 4. HEPEs buffer (2×): 50 mMHEPEs, 20 mM MgCl₂, 0.1 mM MnCl₂, 0.2 mM Na₃VO₄, adjusted to pH of 7.4with NaOH;

5. PGT, Sigma, Cat#P0275): 2 mg/ml of stock solution was prepared bydissolving PBS, reserved at −20° C.

6. ATP: 4 nM of stock solution was prepared by dissolving ddH₂O,reserved at −20° C.;

7. Mice anti-phosphorylation tyrosine-HRP: Invitrogen-037720, 0.5 mg/ml,reserved at 4° C.;

8. TMB: Cell Signaling Tech, Cat #7004L;

9. DTT: 2.5 M of stock solution was prepared with ddH₂O, reserved at−20° C. Before use, 2×HEPEs buffer was added in the solution to thefinal concentration of 1.25 mM.

III. Assay Equipment

1. ELIASA, Bio-Rad, Model-680;

2. Plate washer, Bio-Rad, Model-1575;

3. 4° C. refrigerator, Frestech, Model-BCD-213KC;

4. Micro oscillator, Shanghai Yarong Biochemisty Instrument Plant, ModelMM-I;

5. −80° C. refrigerator, Haier, Model DW-86L386.

IV. Assay Process

1. 2 mg/ml of PGT was diluted with PBS to 0.2 mg/ml. 60 μl of theresulting solution was added in each well. The elisa plate was placed ina refrigerator at 4° C. and coated overnight;

2. The coating solution was discarded to stop the coating. The plate waswashed four times with PBS, and then beaten to dryness;

3. The elisa plate was placed in a refrigerator at 4° C., drained outand stood for 3 h.

4. 2 nM of aqueous solution of each compound was diluted with ddH₂O to adesirable concentration. Then, the solution was added in thecorresponding elisa well by 25 μl/well;

5. 2 nM of ATP solution was diluted with ddH₂O to 25 folds and thensufficiently mixed. The resulting solution was separately added in eachelisa well by 25 μl per well (25 μl ddH₂O was added in the negativecontrol);

6. Her2 kinase was diluted with 2×TKB to 800 folds. The resultingsolution was added in the elisa well by 50 μl per well. Then, the enzymereaction began. Moreover, the elisa plate was immediately placed in amicro-oscillator. The reaction is carried out for 8 min at thetemperature of 4° C.;

7. 2% of SDS was added in the elisa well to stop the reaction by adding100 μl of SDS in each well. The solution was sufficiently mixed on themicro-oscillator to sufficiently mix for about 5 min;

8. The reaction solution was sucked out. The plate was washed four timeswith PBST. After the plate was beaten to dryness, 0.25 μg/ml of miceanti-phosphorylation tyrosine-HRP which was diluted with confiningliquid was added in the plate by 100 μl per well, and then reacted for30 min at the room temperature.

9. The antibody reaction solution was sucked out. The plate was washedsix times with PBST. After the plate was beaten to dryness, TMBperoxidase substrate was added in the plate with 100 al/well, and thenreacted in the dark for 15 min at the room temperature;

10. 100 μl of 2N H₂SO₄ was added in the solution to stop the chromogenicreaction. After the bubbles were cleansed, the solution was measured inelisa at 450 nm.

V. Data Processing Method

OD values were converted in relative inhibition ratios according tofollowing formula:

Relative inhibition ratio=[1−(experiment values−NC mean values)/(PC meanvalues−NC mean values)]×100%

wherein:

PC: Group of cells that grow normally in control wells without acompound;

NC: Blank group without a compound and cells.

The inhibition activity of some compounds on Her-2 were measured asgiven in Table 2.

TABLE 20 Inhibition Activity (EC₅₀) of Some Compounds in Examples onHer-2 EC₅₀ EC₅₀ EC₅₀ Compounds (μM) Compounds (μM) Compounds (μM)Example 4 161 Example 5 96 Example 9 221 Example 21 234 Example 42 291Example 138 244 Example 140 110

In view of the above, the compounds of the invention have excellentinhibition activity on receptor tyrosine kinase, especially erbB family,more specially EGFR and Her 2.

All the patents, patent application publications, patent applicationsand non-patent publications cited in the present description areincorporated herein by reference in their entirety.

From the forging, it will be appreciated, although specific embodimentsof the present invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the present invention. Therefore, the scope ofthe present invention is only defined by the pending claims.

What is claimed is:
 1. A compound of formula I, a stereoisomer thereof,a cis-trans-isomer thereof, a tautomer thereof, or a mixture thereof, ora pharmaceutically acceptable salt thereof, a solvate thereof or aprodrug thereof,

wherein: R¹ is selected from the group consisting of substituted orunsubstituted alkylacylamino, substituted or unsubstitutedalkenylacylamino, substituted or unsubstituted alkynylacylamino,substituted or unsubstituted arylacylamino, substituted or unsubstitutedamino, and substituted or unsubstituted alkoxy; R² and R³ are eachindependently selected from the group consisting of hydrogen,substituted or unsubstituted aralkyl, substituted or unsubstituted aryl,and substituted or unsubstituted heteroaryl; or R² and R³ together withnitrogen atom to which they are attached form substituted orunsubstituted heterocyclyl; and R⁴ is substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted heteroaryl.
 2. A compoundof formula I, a stereoisomer thereof, a cis-trans-isomer thereof, atautomer thereof, or a mixture thereof, or a pharmaceutically acceptablesalt thereof, a solvate thereof or a prodrug thereof,

wherein: R¹ is selected from the group consisting of C₁-C₆alkylacylamino, C₂-C₆ alkenylacylamino, C₂-C₆ alkynylacylamino, C₆-C₁₈arylacylamino, C₁-C₆ alkyl substituted amino, and C₁-C₆ alkoxy; R² andR³ are each independently selected from the group consisting ofhydrogen, C₇-C₂₄ aralkyl, substituted or unsubstituted C₆-C₁₈ aryl, andsubstituted or unsubstituted C₅-C₁₈ heteroaryl, wherein a substituent onthe aryl is selected from the group consisting of C₂-C₆ alkynyl,halogen, C₇-C₂₄ aralkyloxy, C₆-C₂₄ heteroaralkyloxy, C₆-C₁₈ aryloxy, andC₅-C₈ heteroaryloxy, and a substituent on the heteroaryl is selectedfrom the group consisting of C₇-C₂₄ aralkyl, C₆-C₁₈ arylacylamino,C₆-C₁₈ arylsulfonylamino, C₅-C₁₈ heteroarylacylamino, C₃-C₁₀cycloalkylacylamino, C₆-C₁₈ arylaminoacyl, C₇-C₂₄ aralkyloxy, C₆-C₂₄heteroaralkyloxy, and C₆-C₁₈ aryloxy; or R² and R³ together withnitrogen atom to which they are attached form substituted orunsubstituted C₃-C₁₈ heterocyclyl; and R⁴ is substituted orunsubstituted C₃-C₁₈ heterocyclyl, or substituted or unsubstituted C₅-C₈heteroaryl.
 3. The compound of claim 1 or 2, wherein R⁴ istetrahydrofuranyl.
 4. The compound of any one of claims 1 to 3, astereoisomer thereof, a cis-trans-isomer thereof, a tautomer thereof, ora mixture thereof, or a pharmaceutically acceptable salt thereof, asolvate thereof or a prodrug thereof, wherein: R¹ is selected from thegroup consisting of C₁-C₆ alkylacylamino, C₂-C₆ alkenylacylamino, C₂-C₆alkynylacylamino, C₆-C₁₈ arylacylamino, C₁-C₆ alkyl substituted amino,and C₁-C₆ alkoxy; and one of R² and R³ is H, while the other one isselected from the group consisting of C₇-C₂₄ aralkyl, substituted orunsubstituted C₆-C₁₈ aryl, and substituted or unsubstituted C₅-C₈heteroaryl, wherein a substituent on the aryl is selected from the groupconsisting of C₂-C₆ alkynyl, halogen, C₇-C₂₄ aralkyloxy, C₆-C₂₄heteroaralkyloxy, C₆-C₁₈ aryloxy and C₅-C₁₈ heteroaryloxy, and asubstituent on the heteroaryl is selected from the group consisting ofC₇-C₂₄ aralkyl, C₆-C₁₈ arylacylamino, C₆-C₁₈ arylsulfonylamino, C₅-C₁₈heteroarylacylamino, C₃-C₁₀ cycloalkylacylamino, C₆-C₁₈ arylaminoacyl,C₇-C₂₄ aralkyloxy, C₆-C₂₄ heteroaralkyloxy and C₆-C₁₈ aryloxy.
 5. Thecompound of any one of claims 1 to 4, a stereoisomer thereof, acis-trans-isomer thereof, a tautomer thereof, or a mixture thereof, or apharmaceutically acceptable salt thereof, a solvate thereof or a prodrugthereof, wherein: R¹ is selected from the group consisting of C₁-C₆alkylacylamino, C₂-C₆ alkenylacylamino, and C₆-C₁₈ arylacylamino; andone of R² and R³ is H, while the other one is selected from the groupconsisting of C₇-C₂₄ aralkyl, and substituted or unsubstituted C₆-C₁₈aryl, wherein a substituent on the aryl is selected from the groupconsisting of C₂-C₆ alkynyl, halogen, C₇-C₂₄ aralkyloxy, C₆-C₁₈ aryloxy,C₅-C₁₈ heteroaryloxy, and C₆-C₂₄ heteroaralkyloxy.
 6. The compound ofany one of claims 1 to 5, a stereoisomer thereof, a cis-trans-isomerthereof, a tautomer thereof, or a mixture thereof, or a pharmaceuticallyacceptable salt thereof, a solvate thereof or a prodrug thereof,wherein: R¹ is C₂-C₆ alkenylacylamino; and one of R² and R³ is H, whilethe other one is selected from the group consisting of C₇-C₂₄ aralkyl,and substituted or unsubstituted C₆-C₁₈ aryl, wherein a substituent onthe aryl is selected from the group consisting of C₂-C₆ alkynyl,halogen, C₇-C₂₄ aralkyloxy, and C₆-C₂₄ heteroaralkyloxy.
 7. The compoundof any one of claims 1 to 6, a stereoisomer thereof, a cis-trans-isomerthereof, a tautomer thereof, or a mixture thereof, or a pharmaceuticallyacceptable salt thereof, a solvate thereof or a prodrug thereof,wherein: R¹ is selected from the group consisting of4-(dimethylamino)-but-2-enamido, 4-(diethylamino)-but-2-enamido,4-(piperidin-1-yl)-but-2-enamido, 4-(morpholin-4-yl)-but-2-enamido,4-(tert-butylamino)-but-2-enamido, 4-(benzylamino)-but-2-enamido,4-(N-methylbenzylamino)-but-2-enamido,4-(6-hydroxyhexylamino)-but-2-enamido,4-(2-methoxylethylamino)-but-2-enamido,2-(piperidin-4-ylidene)acetamido,2-(1-methylpiperidin-4-ylidene)acetamido,2-(1-ethylpiperidin-4-ylidene)acetamide,2-(1-(2-methoxyehtyl)piperdin-4-ylidene)acetamido,4-(diethanolamino)-but-2-enamido, 4-(N-methylmethoxylethylamino)-but-2-enamido, 4-(N-methylethanolamino)-but-2-enamido,4-(dimethoxyl ethyl amino)-but-2-enamido,4-(N-methyl-6-amino-1-hexanolyl)-but-2-enamido, acrylamido,but-2-enamido, 3-methyl-but-2-enamido, and2-(pyrrolidin-3-ylidene)acetamido.
 8. The compound of any one of claims1 to 6, a stereoisomer thereof, a cis-trans-isomer thereof, a tautomerthereof, or a mixture thereof, or a pharmaceutically acceptable saltthereof, a solvate thereof or a prodrug thereof, wherein: R¹ is selectedfrom the group consisting of C₁-C₆ alkylacylamino, C₂-C₆alkenylacylamino, and C₆-C₁₈ arylacylamino; and one of R² and R³ is H,while the other one is substituted or unsubstituted C₆-C₁₈ aryl, whereina substituent on the aryl is selected from the group consisting ofhalogen, C₆-C₂₄ heteroaralkyloxy, C₂-C₆ alkynyl, and C₇-C₂₄ aralkyloxy.9. The compound of any one of claims 1 to 3, a stereoisomer thereof, acis-trans-isomer thereof, a tautomer thereof, or a mixture thereof, or apharmaceutically acceptable salt thereof, a solvate thereof or a prodrugthereof, wherein: R¹ is C₂-C₆ alkenylacylamino; and R² and R³ togetherwith nitrogen atom to which they are attached form substituted orunsubstituted C₃-C₁₈ heterocyclyl.
 10. The compound of claim 9, astereoisomer thereof, a cis-trans-isomer thereof, a tautomer thereof, ora mixture thereof, or a pharmaceutically acceptable salt thereof, asolvate thereof or a prodrug thereof, wherein: R¹ is2-(piperidin-4-ylidene)acetamide.
 11. A compound of formula I, astereoisomer thereof, a cis-trans-isomer thereof, a tautomer thereof, ora mixture thereof, or a pharmaceutically acceptable salt thereof, asolvate thereof or a prodrug thereof,

wherein: R¹ is C₂-C₆ alkenylacylamino; one of R² and R³ is H, while theother one is selected from the group consisting of substituted orunsubstituted C₆-C₁₈ aryl, and substituted or unsubstituted C₅-C₁₈heteroaryl, wherein a substituent on the aryl is selected from the groupconsisting of C₂-C₆ alkynyl, halogen, C₇-C₂₄ aralkyloxy, and C₆-C₁₈aryloxy, and a substituent on the heteroaryl is selected from the groupconsisting of C₇-C₂₄ aralkyloxy, and C₆-C₁₈ aryloxy; and R⁴ ishexahydropyridinyl optionally substituted with C₁-C₆ alkyl.
 12. Thecompound of claim 11, a stereoisomer thereof, a cis-trans-isomerthereof, a tautomer thereof, or a mixture thereof, or a pharmaceuticallyacceptable salt thereof, a solvate thereof or a prodrug thereof,wherein: R¹ is 2-(piperidin-4-ylidene)acetamide; and one of R² and R³ isH, while the other one is selected from the group consisting ofsubstituted or unsubstituted C₆-C₁₈ aryl, and substituted orunsubstituted C₅-C₁₈ heteroaryl, wherein a substituent on the aryl isselected from the group consisting of C₂-C₆ alkynyl, halogen, C₇-C₂₄aralkyloxy, and C₆-C₁₈ aryloxy, and a substituent on the heteroaryl isC₇-C₂₄ aralkyloxy.
 13. The compound of claim 11, a stereoisomer thereof,a cis-trans-isomer thereof, a tautomer thereof, or a mixture thereof, ora pharmaceutically acceptable salt thereof, a solvate thereof or aprodrug thereof, wherein: R¹ is 2-(pyrrolidin-3-ylidene)acetamido; andone of R² and R³ is H, while the other one is C₅-C₁₈ heteroarylsubstituted with C₆-C₁₈ aryloxy, or substituted or unsubstituted C₆-C₁₈aryl, wherein a substituent on the aryl is selected from the groupconsisting of C₂-C₆ alkynyl, halogen, C₇-C₂₄ aralkyloxy, and C₆-C₁₈aryloxy, and a substituent on the heteroaryl is C₇-C₂₄ aralkyloxy.
 14. Acompound of formula I, a stereoisomer thereof, a cis-trans-isomerthereof, a tautomer thereof, or a mixture thereof, or a pharmaceuticallyacceptable salt thereof, a solvate thereof or a prodrug thereof,

wherein: R¹ is C₂-C₆ alkenylacylamino; one of R² and R³ is H, while theother one is selected from the group consisting of substituted orunsubstituted C₆-C₁₈ aryl, and substituted or unsubstituted C₅-C₁₈heteroaryl, wherein a substituent on the aryl is selected from the groupconsisting of C₂-C₆ alkynyl, halogen, C₇-C₂₄ aralkyloxy, C₆-C₂₄heteroaralkyloxy, and C₆-C₁₈ aryloxy, and a substituent on theheteroaryl is selected from the group consisting of C₇-C₂₄ aralkyloxyand C₆-C₁₈ aryloxy; and R⁴ is pyridinyl.
 15. The compound of claim 14, astereoisomer thereof, a cis-trans-isomer thereof, a tautomer thereof, ora mixture thereof, or a pharmaceutically acceptable salt thereof, asolvate thereof or a prodrug thereof, wherein: R¹ is2-(piperidin-4-ylidene)acetamido; and one of R² and R³ is H, while theother one is selected from the group consisting of substituted orunsubstituted C₆-C₁₈ aryl, and substituted or unsubstituted C₅-C₁₈heteroaryl, wherein a substituent on the aryl is selected from the groupconsisting of C₂-C₆ alkynyl, halogen, C₇-C₂₄ aralkyloxy, C₆-C₂₄heteroaralkyloxy, and C₆-C₁₈ aryloxy, and a substituent on theheteroaryl is selected from the group consisting of C₇-C₂₄ aralkyloxy,and C₆-C₁₈ aryloxy.
 16. The compound of claim 14, a stereoisomerthereof, a cis-trans-isomer thereof, a tautomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, a solvatethereof or a prodrug thereof, wherein: R¹ is2-(pyrrolidin-3-ylidene)acetamido; and one of R² and R³ is H, while theother one is C₅-C₁₈ heteroaryl substituted with C₆-C₁₈ aryloxy.
 17. Thecompound of claim 14, a stereoisomer thereof, a cis-trans-isomerthereof, a tautomer thereof, or a mixture thereof, or a pharmaceuticallyacceptable salt thereof, a solvate thereof or a prodrug thereof,wherein: R¹ is 4-(diethyl amino)-but-2-eneamido; and one of R² and R³ isH, while the other one is C₆-C₁₈ aryl substituted with halogen.
 18. Acompound of formula I, a stereoisomer thereof, a cis-trans-isomerthereof, a tautomer thereof, or a mixture thereof, or a pharmaceuticallyacceptable salt thereof, a solvate thereof or a prodrug thereof,

wherein the compound is selected from the group consisting of:(E)-4-bromo-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)but-2-enamide;(E)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamidehydrochloride;(E)-N-(4-(3-chloro-4-fluorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(4-(4-(benzyloxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(4-(3-bromophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(4-(4-(2-fluorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(4-(4-(2-chlorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(4-(4-(3-chlorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(4-(4-(benzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(4-(4-(2-cyanobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(4-(4-(4-tert-butylbenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(4-(4-(3-cyanobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(4-(4-(4-chlorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(4-(4-(2-methylbenzyloxy)-3-chiorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(4-(4-(3-methylbenzyloxy)-3-chiorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(4-(4-(4-methylbenzyloxy)-3-chiorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-3-cyano-4-((R)-1-phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)acrylamide;(E)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)but-2-enamide;N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-3-methylbut-2-enamide;N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)propiolamide;N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)propionamide;N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)acetamide;N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)benzamide;tert-butyl 4-(2-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl-amino)-2-oxoethylidene)piperidine-1-carboxylate;N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(1-methylpiperidin-4-ylidene)acetamide;N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(1-ethylpiperidin-4-ylidene)acetamide;2-(1-benzylpiperidin-4-ylidene)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)acetamide;N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(1-(2-methoxyethyl)piperidin-4-ylidene)acetamide; methyl2-(4-(2-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl-amino)-2-oxoethylidene)piperidin-1-yl)acetate;N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(1-isopropylpiperidin-4-ylidene)acetamide;N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(1-(2-hydroxyethyl)piperidin-4-ylidene)acetamide;(E/Z)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(pyrrolidin-3-ylidene)acetamide;N¹-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-N⁴-(2-(2-(dimethylamino)ethoxy)ethyl)fumaramide;N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(1-(2-(2-(2-hydroxyethoxy)ethylamino)acetyl)piperidin-4-ylidene)acetamide;N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(1-(methylsulfonyl)piperidin-4-ylidene) acetamide; N-(4-(3-chloro-4-fluorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(3-bromophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(2-fluorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(4-fluorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(2-chlorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(3-chlorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(4-chlorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(2-methylbenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(3-methylbenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(4-methylbenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(2-methoxybenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(3-methoxybenzyloxy)-3-chiorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(4-methoxybenzyloxy)-3-chiorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(2-cyanobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(3-cyanobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(4-cyanobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(4-tert-butylbenzyloxy)-3-chiorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(benzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(2-chlorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(3-chlorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(4-chlorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-4-((S)-1-phenylethylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-4-((R)-1-phenylethylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(1-benzyl-1H-indol-5-yl-amino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(1-(3-cyanobenzyl)-1H-indol-5-yl-amino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(1-(3-methoxybenzyl)-1H-indol-5-yl-amino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(1-(3-chlorobenzyl)-1H-indol-5-yl-amino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-4-(indolin-1-yl)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(6-chloroindolin-1-yl)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-4-(6-fluoroindolin-1-yl)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-chloroindolin-1-yl)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-4-(3,4-dihydroquinolin-1(2H)-yl)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-4-(6-methyl-3,4-dihydroquinolin-1(2H)-yl)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-7-(tetrahydrofuran-3-yl-oxy)-4-(7-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(6-(benzyloxy)indolin-1-yl)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide; methyl1-(3-cyano-6-(2-(piperidin-4-ylidene)acetamido)-7-(tetrahydrofuran-3-yl-oxy)quinolin-4-yl)-indoline-2-carboxylate;N-(3-cyano-4-(2-(hydroxymethyl)indolin-1-yl)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(6-(1H-pyrrol-1-yl)indolin-1-yl)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-4-(octahydroindol-1-yl)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-4-(pyrimidin-2-yl-amino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(2-(3-cyano-6-(2-(piperidin-4-ylidene)acetamido)-7-(tetrahydrofuran-3-yl-oxy)quinolin-4-yl-amino)pyrimidin-5-yl)benzamide;N-(2-(3-cyano-6-(2-(piperidin-4-ylidene)acetamido)-7-(tetrahydrofuran-3-yl-oxy)quinolin-4-yl-amino)pyrimidin-5-yl)-4-(dimethylamino)benzamide;N-(3-cyano-4-(5-(phenylsulfonamido)pyrimidin-2-yl-amino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(5-(3-cyano-6-(2-(piperidin-4-ylidene)acetamido)-7-(tetrahydrofuran-3-yl-oxy)quinolin-4-yl-amino)pyrimidin-2-yl)benzamide;N-(5-(3-cyano-6-(2-(piperidin-4-ylidene)acetamido)-7-(tetrahydrofuran-3-yl-oxy)quinolin-4-yl-amino)pyrimidin-2-yl)furan-2-carboxamide;N-(5-(3-cyano-6-(2-(piperidin-4-ylidene)acetamido)-7-(tetrahydrofuran-3-yl-oxy)quinolin-4-yl-amino)pyrimidin-2-yl)thiophene-2-carboxamide;N-(5-(3-cyano-6-(2-(piperidin-4-ylidene)acetamido)-7-(tetrahydrofuran-3-yl-oxy)quinolin-4-yl-amino)pyrimidin-2-yl)cyclohexylcarboxamide;5-(3-cyano-6-(2-(piperidin-4-ylidene)acetamido)-7-(tetrahydrofuran-3-yl-oxy)quinolin-4-yl-amino)-N-(4-methoxyphenyl)pyrimidin-2-carboxamide;N-(3-cyano-4-(pyridin-2-yl-amino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;6-(3-cyano-6-(2-(piperidin-4-ylidene)acetamido)-7-(tetrahydrofuran-3-yl-oxy)quinolin-4-yl-amino)-N-(4-methoxyphenyl)nicotinamide;N-(3-cyano-4-(pyridin-3-yl-amino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-4-(pyridin-4-yl-amino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(6-(benzyloxy)pyridin-3-yl-amino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-4-(pyrazin-2-yl-amino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(3-chloro-4-fluorophenylamino)-3-cyano-7-(1-methylpiperidin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-4-(3-ethynylphenylamino)-7-(1-methylpiperidin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(benzyloxy)-3-chlorophenylamino)-3-cyano-7-(1-methylpiperidin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(2-chlorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(1-methylpiperidin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(3-chlorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(1-methylpiperidin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(4-chlorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(1-methylpiperidin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(4-bromobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(1-methylpiperidin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(4-methylbenzyloxy)-3-chlorophenylamino)-3-cyano-7-(1-methylpiperidin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(4-methoxybenzyloxy)-3-chiorophenylamino)-3-cyano-7-(1-methylpiperidin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(4-cyanobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(1-methylpiperidin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(4-ethylbenzyloxy)-3-chlorophenylamino)-3-cyano-7-(1-methylpiperidin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(4-ethoxybenzyloxy)-3-chlorophenylamino)-3-cyano-7-(1-methylpiperidin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(3-chloro-4-phenoxyphenylamino)-3-cyano-7-(1-methylpiperidin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-7-(1-methylpiperidin-4-yl-oxy)-4-(pyridin-2-yl-amino)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-7-(1-methylpiperidin-4-yl-oxy)-4-(pyridin-3-yl-amino)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-7-(1-methylpiperidin-4-yl-oxy)-4-(pyridin-4-yl-amino)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(6-(benzyloxy)pyridin-3-yl-amino)-3-cyano-7-(1-methylpiperidin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(3-chloro-4-fluorophenylamino)-3-cyano-7-(pyridin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-4-(3-ethynylphenylamino)-7-(pyridin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-4-(4-phenoxyphenylamino)-7-(pyridin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(benzyloxy)phenylamino)-3-cyano-7-(pyridin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(2-chlorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(pyridin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(4-methylbenzyloxy)-3-chlorophenylamino)-3-cyano-7-(pyridin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(4-methoxybenzyloxy)phenyl amino)-3-cyano-7-(pyridin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(4-(3-cyanobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(pyridin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-4-(pyridine-2-yl-amino)-7-(pyridin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-7-(pyridin-4-yl-oxy)-4-(pyrimidin-2-yl-amino)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(6-(benzyloxy)pyridin-3-yl-amino)-3-cyano-7-(pyridin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide; N-(4-(6-(3-chlorobenzyloxy)pyridin-3-yl-amino)-3-cyano-7-(pyridin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(3-cyano-4-(6-(phenoxypyridin-3-yl-amino)-7-(pyridin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;N-(4-(3-chloro-4-(pyridine-2-yl-methoxy)phenylamino)-3-cyano-7-(pyridin-4-yl-oxy)quinolin-6-yl)-2-(piperidin-4-ylidene)acetamide;(E/Z)-N-(3-cyano-4-(6-(phenoxypyridin-3-yl-amino)-7-(pyridin-4-yl-oxy)quinolin-6-yl)-2-(pyrrolidin-3-ylidene)acetamide;(E/Z)-N-(3-cyano-7-(1-methylpiperidin-4-yl-oxy)-4-(6-(phenoxypyridin-3-yl-amino)quinolin-6-yl)-2-(pyrrolidin-3-ylidene)acetamide;(E/Z)-N-(3-cyano-4-(6-(phenoxypyridin-3-yl-amino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-2-(pyrrolidin-3-ylidene)acetamide;4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-6-methoxy-7-(tetrahydrofuran-3-yl-oxy)quinoline-3-carbonitrile;4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-6-(piperidin-1-yl)-7-(tetrahydrofuran-3-yl-oxy)quinoline-3-carbonitrile;4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-6-(2-methoxyethoxy)-7-(tetrahydrofuran-3-yl-oxy)quinoline-3-carbonitrile;4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-6-(2-(2-methoxyethoxy)ethoxy)-7-(tetrahydrofuran-3-yl-oxy)quinoline-3-carbonitrile;4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-6-(2-morpholinoethoxy)-7-(tetrahydrofuran-3-yl-oxy)quinoline-3-carbonitrile;(S,E)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(R,E)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylaimino)-but-2-enamide;(R,E)-N-(3-cyano-4-(3-ethynylphenyl amino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylaimino)-but-2-enamide;(S,E)-N-(4-(3-chloro-4-fluorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(diethylamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(piperidin-1-yl)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(morpholin-4-yl)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(tert-butylaimino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(benzylamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(6-hydroxyhexylaimino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(N-methylbenzylamino)-but-2-enamide;(S,E)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(diethylamino)-but-2-enamide;(S,E)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(piperidin-1-yl)-but-2-enamide;(S,E)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(morpholin-4-yl)-but-2-enamide;(S,E)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(tert-butylamino)-but-2-enamide;(S,E)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(6-hydroxyhexylamino)-but-2-enamide;(S,E)-N-(4-(4-(benzyloxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(S,E)-N-(4-(3-bromophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(S,E)-N-(4-(4-(2-fluorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(S,E)-N-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(S,E)-N-(4-(4-(2-chlorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylaimino)-but-2-enamide;(S,E)-N-(4-(4-(3-chlorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylaimino)-but-2-enamide;(S,E)-N-(4-(4-(benzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(S,E)-N-(4-(4-(2-cyanobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(S,E)-N-(4-(4-(4-tert-butylbenzyloxy)-3-chiorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(S,E)-N-(4-(4-(3-cyanobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(S,E)-N-(4-(4-(4-chlorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylaimino)-but-2-enamide;(S,E)-N-(4-(4-(2-methylbenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(S,E)-N-(4-(4-(4-methylbenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(S,E)-N-(4-(3-chloro-4-fluorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(diethylamino)-but-2-enamide;(S,E)-N-(4-(3-chloro-4-fluorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(piperidin-1-yl)-but-2-enamide;(S,E)-N-(4-(3-chloro-4-fluorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(morpholin-4-yl)-but-2-enamide;(S,E)-N-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(diethylamino)-but-2-enamide;(S,E)-N-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(piperidin-1-yl)-but-2-enamide;(S,E)-N-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(morpholin-4-yl)-but-2-enamide;(E)-N-(4-(3-chloro-4-fluorophenylamino)-3-cyano-7-(pyridin-3-yl-oxy)quinolin-6-yl)4-(dimethylamino)-but-2-enamide;(E/Z)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylaimino)-but-2-enamide;(E/Z)-N-(4-(3-chloro-4-fluorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E/Z)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylaimino)-but-2-enamide;(E/Z)-N-(4-(4-(benzyloxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylaimino)-but-2-enamide;(E/Z)-N-(4-(3-bromophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(E/Z)-N-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethylamino)-but-2-enamide;(S,E/Z)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(diethylamino)-but-2-enamide;(S,E/Z)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(piperidin-1-yl)-but-2-enamide;(S,E/Z)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(morpholin-4-yl)-but-2-enamide;(S,E/Z)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(diethylamino)-but-2-enamide;(S,E/Z)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(piperidin-1-yl)-but-2-enamide;(S,E/Z)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(morpholin-4-yl)-but-2-enamide;(S,E/Z)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-3-cyano-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(2-methoxyethylamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(diethanolamino)-but-2-enamide(S,E)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(N-methylmethoxyethylamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(N-methylethanolamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethoxyethylamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-ethynylphenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(N-methyl-6-amino-1-hexanolyl)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-chloro-4-fluoro-phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(diethanolamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-chloro-4-fluoro-phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(N-methylmethoxyethylamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-chloro-4-fluoro-phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(N-methylethanolamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-chloro-4-fluoro-phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethoxyethylamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-chloro-4-fluoro-phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(N-methyl-6-amino-1-hexanolyl)-but-2-enamide;(S,E)-N-(3-cyano-4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(diethanolamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(N-methylmethoxyethylamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(N-methylethanolamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethoxyethylamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(N-methyl-6-amino-1-hexanolyl)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(diethanolamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(N-methylmethoxyethylamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(N-methylethanolamino)-but-2-enamide;(S,E)-N-(3-cyano-4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(dimethoxyethylamino)-but-2-enamide;and(S,E)-N-(3-cyano-4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-6-yl)-4-(N-methyl-6-amino-1-hexanol)-but-2-enamide.19. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of any one of claims 1 to 18, a stereoisomerthereof, a cis-trans-isomer thereof, a tautomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, a solvatethereof or a prodrug thereof, and a pharmaceutically acceptable carrier.20. A method for treating and/or preventing tumor in a mammal,comprising administering to the mammal in need thereof a therapeuticallyeffective amount of a compound of any one of claims 1 to 18, astereoisomer thereof, a cis-trans-isomer thereof, a tautomer thereof, ora mixture thereof, or a pharmaceutically acceptable salt thereof, asolvate thereof or a prodrug thereof.
 21. The method of claim 20,wherein the mammal is human.
 22. The method of claim 20, whereinreceptor tyrosine kinase in tumor occurs overexpression or mutation. 23.The method of claim 22, wherein the receptor tyrosine kinase is erbBfamily.
 24. The method of claim 23, wherein the erbB family is selectedfrom EGFR and/or Her2.
 25. A method for inhibiting growth of tumorcells, comprising contacting the tumor cells with a therapeuticallyeffective amount of a compound of any one of claims 1 to 18, astereoisomer thereof, a cis-trans-isomer thereof, a tautomer thereof, ora mixture thereof, or a pharmaceutically acceptable salt thereof, asolvate thereof or a prodrug thereof.
 26. The method of claim 25,wherein a receptor tyrosine kinase in the tumor cells occursoverexpression or mutation.
 27. The method of claim 26, wherein thereceptor tyrosine kinase is erbB family.
 28. The method of claim 27,wherein the erbB family is selected from EGFR and/or Her2.
 29. A methodfor inhibiting overexpression or mutantion of a receptor tyrosine kinasein a mammal, comprising contacting the receptor tyrosine kinase with atherapeutically effective amount of a compound of any one of claims 1 to18, a stereoisomer thereof, a cis-trans-isomer thereof, a tautomerthereof, or a mixture thereof, or a pharmaceutically acceptable saltthereof, a solvate thereof or a prodrug thereof.
 30. The method of claim29, wherein the receptor tyrosine kinase is erbB family.
 31. The methodof claim 30, wherein the erbB family is selected from EGFR and/or Her2.32. A method for treating and/or preventing physiological abnormitycaused by overexpression or mutation of a receptor tyrosine kinase in amammal, comprising administering to the mammal in need thereof atherapeutically effective amount of a compound of any one of claims 1 to18, a stereoisomer thereof, a cis-trans-isomer thereof, a tautomerthereof, or a mixture thereof, or a pharmaceutically acceptable saltthereof, a solvate thereof or a prodrug thereof.
 33. The method of claim32, wherein the receptor tyrosine kinase is erbB family.
 34. The methodof claim 33, wherein the erbB family is selected from EGFR and/or Her2.35. The method of any one of claims 32 to 34, wherein the physiologicalabnormity is tumor.